CN106536518B - Anthelmintic compounds - Google Patents

Anthelmintic compounds Download PDF

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CN106536518B
CN106536518B CN201580034873.7A CN201580034873A CN106536518B CN 106536518 B CN106536518 B CN 106536518B CN 201580034873 A CN201580034873 A CN 201580034873A CN 106536518 B CN106536518 B CN 106536518B
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haloalkyl
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CN106536518A (en
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A·朗
S·R·古拉拉
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Boehringer Ingelheim Animal Health USA Inc
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    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
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  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to novel anthelmintic compounds of formula (I):
Figure DDA0001193146040000011
wherein Y and Z are independently a bicyclic carbocyclic or bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic or heteroaryl, the variable X1、X6、X8、Q1、Q2、Q3、Q4、Q5、Q6Ring A, ring B, W, W', R2、R3R, R', m, n and q are as defined herein. The invention also provides veterinary compositions comprising the anthelmintic compounds of the invention, and uses thereofFor the treatment and prevention of parasitic infections in animals.

Description

Anthelmintic compounds
Cross Reference to Related Applications
This application claims priority to U.S. provisional patent application No. 62/000,256 filed on 5/19/2014, which is incorporated herein by reference in its entirety.
Introduction by reference
The foregoing applications and all documents cited therein or during the prosecution thereof ("application cited documents") and all documents cited or referenced in application cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, and any manufacturer's instructions, specifications, product specifications, and product sheets for any product mentioned herein or in any document incorporated by reference herein, are hereby incorporated by reference herein and may be used in the practice of the present invention.
Technical Field
The present invention relates to novel anthelmintic compounds of formula (I) and compositions comprising them:
Figure BDA0001193146030000011
wherein at least one of the variables Y and Z is a bicyclic carbocyclyl or heterocyclyl group. Variable Y, X1、X2、X3、X4、X5、X6、X7、X8And Z is defined as follows, wherein X2Or X7Is a linker L19, L20 or L21 as defined herein. The invention also relates to parasiticidal compositions comprising said compounds, and to methods and uses of said compounds for the treatment and prevention of parasitic infections and infestations in animals.
Background
Animals such as mammals and birds are often susceptible to parasite infestation/infection. These parasites may be ectoparasites (such as insects) and endoparasites (such as nematodes and other worms). Livestock (such as cats and dogs) are often infested with one or more of the following ectoparasites: fleas (Ctenocephalides spp.) such as Ctenocephalides felis (Ctenocephalides felis), etc.;
ticks (e.g., Rhipicephalus spp.), hard ticks spp, Dermacentor spp, Haematoloma spp, and the like);
mites (e.g., Demodex spp.), Sarcoptes spp, otoptes spp, and the like;
lice (e.g., louse (trichoectes spp.), acantho (cheyletellla spp.), lingonanthus spp., etc.);
mosquitoes (Aedes spp.), Culex spp, Anopheles spp, and the like); and
flies (Hematobia spp.), Musca spp, Silybus (Stomoxysspp.), Dermatobia spp, Cochliomyia spp.
Fleas are a particular problem because they not only adversely affect the health of animals or humans, but also cause a great deal of psychological stress. In addition, fleas can also transmit pathogens, such as tapeworms (dipylidium caninum), to animals and humans.
Similarly, ticks also pose a physical and psychological hazard to animals or humans. However, the most serious problem associated with ticks is that they are vectors of pathogens in both humans and animals. Major diseases transmitted by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or pirlasmosis caused by Babesia spp.) and rickettsialosis (also known as Rocky Mountain spot fever). Ticks also release toxins that cause inflammation or paralysis of the host. Sometimes, these toxins are lethal to the host.
Similarly, farm animals are also susceptible to infestation by parasites. For example, cattle are affected by a large number of parasites. Parasites which are very prevalent in cattle in some areas are ticks of the Rhipicephalus (Rhipicephalus), especially those of the species Boophilus microplus (Boophilus microplus), Decoloatus and Boophilus annulatus. Ticks such as Rhipicephalus microplus (original bovine microplus) are difficult to control because they lay eggs in the pasture of grazing farm animals. This class of ticks is considered to be a single host class of ticks, with both the immature and adult stages spent on one animal, with the female ticks subsequently becoming engorged and shed from the host to lay eggs in the environment. The life cycle of ticks is about 3 to 4 weeks. In addition to cattle, Rhipicephalus microplus can also infest buffalo, horses, donkeys, goats, sheep, deer, pigs and dogs. Heavy tick burdens on animals can reduce yield and damage coat, as well as spread diseases such as babesia ("cattle fever") and anaplastomyis (anaplasia).
Animals and humans also suffer from endogenous parasitic infections including, for example, helminthiasis, which is caused by parasites classified as cestodes (striped worms), nematodes (roundworms), and trematodes (flatworms or trematodes). These parasites adversely affect the nutrition of animals and cause severe economic losses in pigs, sheep, horses and cattle, as well as affecting livestock and poultry. Other parasites present in the gastrointestinal tract of animals and humans include the extra-intestinal stages of hookworm (Ancylostoma), banostomum (Necator), Ascaris (Ascaris), Strongyloides (Strongyloides), Trichinella (trichonella), telangium (Capillaria), Toxocara (Toxocara), Toxocara (Toxascaris), trichuris (trichoris), pinus (Enterobius) and parasites present in blood or other tissues and organs such as filarial and Strongyloides, Toxocara (Toxocara) and trichodera (trichonella).
Another endoparasite that severely damages animals is Heartworm (Heartworm) canis. The most common hosts are dogs and cats, but other animals such as ferrets and raccoons can also be infected. Mosquito bites transmit parasites, which carry heartworm larvae. Adults live in the major blood vessels of the lungs, causing vascular inflammation and potentially leading to cardiac damage and early death. In late stage infection, the worms also enter the heart.
More recently, anthelmintic compounds having activity against various endogenous parasitic species have been reported in WO 2009/077527 a1, WO 2010/115688 a1, WO 2010/146083 a1 and EP 2468096 a1 (all incorporated herein by reference). In addition, US2014/0142114 a1, which is incorporated herein by reference, describes anthelmintic compounds having at least one bicyclic carbocyclic or heterocyclic group. Although many parasitic infections can be treated with known antiparasitic compounds and compositions, there remains a need for new parasiticidal active agents and veterinary compositions and methods with improved efficacy, bioavailability and coverage spectrum to protect animals against endoparasites and/or ectoparasites. The present invention addresses this need.
Brief description of the invention
The present invention is directed to novel and inventive anthelmintic compounds of formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), (IB-4), (IC) and (IC-1) as described herein:
Figure BDA0001193146030000041
Figure BDA0001193146030000051
and compositions comprising said compounds in combination with a pharmaceutically acceptable carrier or diluent, with the proviso that X2Or X7Is a linker L19, L20 or L21 as defined herein or a spirocyclic carbocyclic linker, a heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic linker contains 4,5 or 6 ring atoms.
The invention is also directed to methods for treating and preventing parasitic infections in an animal comprising administering to the animal at least one compound of the invention. The invention also includes the use of the compounds for the treatment and/or prevention of parasitic infections in animals, and the use of the compounds in the manufacture of a medicament for the treatment and/or prevention of parasitic infections in animals.
The compounds of the present invention are intended to encompass racemic mixtures, specific stereoisomers, and tautomeric forms of the compounds. Another aspect of the invention is a salt form of a compound of the invention.
Another aspect of the invention is a solid state form of the compounds of the invention, which consists of crystalline forms including single crystals, nanocrystals, co-crystals, molecular complexes, hydrates, dehydrates, solvates, desolvates, clathrates and inclusion complexes, and amorphous forms including amorphous glasses and amorphous forms.
It is noted that the intent of the present invention is not to encompass within its scope any previously disclosed product, process of making a product, or method of using a product, in compliance with the written description or requirements of the USPTO (35u.s.c. 112, first paragraph) or EPO (EPC, clause 83), so that applicants reserve the right and disclose herein a disclaimer of any product, process of making a product, or process of using a product described above.
It should be noted that in this disclosure, particularly in the claims and/or paragraphs, terms such as "comprising," "comprises," "comprising," and the like are to be considered as having a meaning in U.S. patent law; for example, they may mean "including" (included), "and the like; and terms such as "consisting essentially of … … (of) and" consisting essentially of … … (of) "have the meaning in U.S. patent law, e.g., they allow for elements not expressly recited, but exclude elements found in the prior art or affecting the basic nature or novelty of the invention.
These and other embodiments are disclosed in or are apparent from and encompassed by the following detailed description.
Detailed Description
The present invention provides novel and inventive anthelmintic compounds of formula (I), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), (IB-4), (IC) and (IC-1) as described herein, as well as compositions comprising said compounds together with a pharmaceutically acceptable carrier or diluent. The compounds of the invention have been found to be highly effective against endoparasites (endoparasites) that cause harm to animals. In some embodiments, the compounds of the invention are also useful for combating ectoparasites (ectoparasites) that cause damage to animals.
The compounds may be combined in compositions with one or more additional active agents to broaden the coverage against both endoparasites and ectoparasites.
Also provided are methods and uses of the compounds and compositions for treating and/or preventing parasitic infections and infestations of an animal comprising administering to the animal an effective amount of a compound or composition of the invention.
Definition of
Unless otherwise indicated, the data used herein have their ordinary meaning in the art. The organic moieties mentioned in the definitions of the variables of formula (I) are-as the term halogen-collective terms for the individual lists of the individual group members. In each case, the prefix Cn-CmRefers to the possible number of carbon atoms in the group.
The term "substituted" as used herein with respect to a formula means that one or more hydrogen atoms on a compound or functional group are replaced with the substituent.
The term "animal" as used herein includes all mammals, birds and fish, and includes all vertebrates. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. It also includes individual animals at all stages of development, including embryonic and fetal stages. In certain embodiments, the animal will be a non-human animal.
As used in this specification, "active agent" or "active ingredient" or "therapeutic agent" refers to the anthelmintic compounds of the invention, unless otherwise specifically indicated or apparent from the context.
The term "fatty acid" refers to carboxylic acids having from 4 to 26 carbon atoms.
The term "fatty alcohol" or "long chain fatty alcohol" refers to an aliphatic alcohol containing from 6 to 20 carbon atoms.
The term "alkylRefers to saturated straight, branched, cyclic, primary, secondary, or tertiary hydrocarbons, including those having from 1 to 20 atoms. In certain embodiments, the alkyl group will include C1-C12、 C1-C10、C1-C8、C1-C6Or C1-C4An alkyl group. C1-C10Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and isomers thereof. C1-C4Alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.
The term "carbocyclyl" refers to a carbocyclic containing system, including "cycloalkyl" and "aryl" groups as defined herein.
Cyclic alkyl groups or "cycloalkyl" groups, which are encompassed by alkyl groups, include those alkyl groups of 3 to 10 carbon atoms having single or multiple fused rings. In certain embodiments, cycloalkyl groups include C4-C7Or C3-C4A cyclic alkyl group. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The alkyl groups described herein may be unsubstituted or substituted with one or more of the following moieties: alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, acyl, acyloxy, sulfanyl, sulfamoyl (sulfamoyl), amino, alkyl-or dialkylamino, acylamino, arylamino, alkoxy, haloalkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid; alkyl, haloalkyl or arylsulfate; alkyl, haloalkyl or arylsulfonyl; an arylalkyl sulfonyl group; alkyl, haloalkyl or arylsulfinyl; (ii) an arylalkyl sulfinyl group; an alkylhaloalkyl or arylthio group; an arylalkylthio group; heteroarylthio, heteroarylalkylthio, heteroarylsulfinyl, heteroarylalkylsulfinyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, alkyl, haloalkyl or aryl esters, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate ester, phosphonate ester, or any other functional group useful without inhibiting the biological activity of the compounds of the present invention, unprotected or protected as needed, as known to those skilled in the art, e.g., as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, 3 rd edition, 1999, incorporated herein by reference.
Various terms, including the term "alkyl" such as "alkylcycloalkyl", "cycloalkylalkyl", "alkylamino", or "dialkylamino" are to be understood as including alkyl groups as defined above attached to other functional groups wherein the groups are attached to the compound through the last group listed, as understood by those skilled in the art.
The term "alkenyl" refers to straight and branched carbon chains having at least one carbon-carbon double bond. In certain embodiments, an alkenyl group may include C2-C20An alkenyl group. In other embodiments, alkenyl includes C2-C12、C2-C10、C2-C8、C2-C6Or C2-C4An alkenyl group. In one embodiment of the alkenyl groupIn another embodiment, the number of double bonds is one or two. Other ranges of carbon-carbon double bonds and carbon number are also contemplated, depending on the position of the alkenyl moiety on the molecule. "C2-C10An-alkenyl "group may comprise more than one double bond in the chain. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 2-methyl-3-butenyl, 1-methyl-2-butenyl, 1, 2-dimethyl-2-butenyl, 1-methyl-2-propenyl, 1, 2-methyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 1, 3-dimethyl-3-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-3-butenyl, 2,2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.
"alkynyl" refers to straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another embodiment of alkenyl, the number of triple bonds is one or two. In certain embodiments, alkynyl groups include C2-C20An alkynyl group. In other embodiments, alkynyl groups may include C2-C12、C2-C10、 C2-C8、C2-C6Or C2-C4An alkynyl group. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. For example, the term "C" as used herein2-C10-alkynyl "means a straight or branched chain unsaturated hydrocarbon group having from 2 to 10 carbon atoms and comprising at least one triple bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-buty-1-yl, N-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-pent-2-yn-5-yl, n-methylbut-1-yn-4-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, N-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.
The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogen atoms. E.g. C1-C4Haloalkyl includes, but is not limited to, chloromethyl, bromoethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromomethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethylEthyl, 2, 2-dichloro-2-fluoroethyl, 2,2, 2-trichloroethyl, pentafluoroethyl and the like.
The term "haloalkenyl" refers to an alkenyl group, as defined herein, which is substituted with one or more halogen atoms.
The term "haloalkynyl" refers to an alkynyl group, as defined herein, which is substituted with one or more halogen atoms.
"alkoxy" refers to alkyl-O-wherein alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "halocycloalkenyloxy", and "halocycloalkenyloxy" refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. C1-C6Examples of-alkoxy include, but are not limited to, methoxy, ethoxy, C2H5-CH2O-、(CH3)2CHO-, n-butoxy, C2H5-CH(CH3)O-、(CH3)2CH-CH2O-、(CH3)3CO-, n-pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1, 2-trimethylpropyloxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like.
The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above. Similarly, the terms "haloalkylthio", "cycloalkylthio", and the like, refer to haloalkyl-S-and cycloalkyl-S-, wherein haloalkyl and cycloalkyl are as defined above.
The term "halothio" refers to (halogen)5-S-, wherein halogen is as defined above. Examples of "halothio" are the groups F5S-。
The term "alkylsulfinyl" refers to alkyl-S (O) -, wherein alkyl is as defined above. Similarly, the term "haloalkylsulfinyl" refers to haloalkyl-s (o) -, wherein haloalkyl is as defined above.
The term "alkylsulfonyl" refers to alkyl-S (O)2-, wherein alkyl is as defined above. Similarly, the term "haloalkylsulfonyl" refers to haloalkyl-S (O)2-, wherein haloalkyl is as defined above.
The terms alkylamino and dialkylamino refer to alkyl-NH-and (alkyl)2N-wherein alkyl is as defined above. Similarly, the term "haloalkylamino" refers to haloalkyl-NH-, wherein haloalkyl is as defined above.
The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C (O) -, alkoxy-C (O) -, alkylamino-C (O) -, and dialkylamino-C (O) -, wherein alkyl, alkoxy, alkylamino, and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" refer to the groups haloalkyl-C (O) -, haloalkoxy-C (O) -, haloalkylamino-C (O) -, and dihaloalkylamino-C (O) -, wherein haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.
"aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple condensed rings. In certain embodiments, the aryl group comprises C6-C10An aryl group. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, biphenylene, fluorene, anthracene, acenaphthene, phenanthrene, and indanyl. Examples of bicyclic aryl groups include naphthyl and indeneAnd (4) filling the base. An aryl group may be unsubstituted or substituted with one or more moieties selected from: halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkenyloxy, haloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, di (alkyl) amino, di (alkenyl) -amino, halo, alkoxy, haloalkynyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, haloalk, Di (alkynyl) amino, or trialkylsilyl.
The term "aralkyl" or "arylalkyl" refers to an alkylene bridge (-CH) through a diradical2-)nAn aryl group bonded to the parent compound, wherein n is 1-12, and wherein "aryl" is as defined above.
"heteroaryl" refers to a monovalent aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, having one or more oxygen, nitrogen and sulfur heteroatoms, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms, in the ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple condensed rings, provided that the point of attachment is through a heteroaryl ring atom. Preferred heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuryl, dihydrobenzofuryl and benzothienyl. The heteroaryl ring may be unsubstituted or substituted with one or more moieties as described for aryl above.
"heterocyclyl", "heterocycle (heterocyclic)" or "heterocycle (heterocyclo)" refers to a fully saturated or unsaturated cyclic group, including, for example, 3 to 8 membered monocyclic, 4 to 7 membered monocyclic, and 5 to 6 membered monocyclic; a 7-to 12-membered bicyclic ring; 10-to 15-membered tricyclic ring; or a 6-12-membered spiro ring system having one or more oxygen, sulfur or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, in the ring. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted with one or more moieties as described for the aryl groups above.
Exemplary monocyclic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazaazaazanyl
Figure BDA0001193146030000131
Z is aza radical
Figure BDA0001193146030000132
Phenyl, 4-piperidinonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxolane, and tetrahydro-1, 1-dioxothienyl, triazolyl, triazinyl, and the like.
Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzo [ d ] isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl, 1,2, 3-benzotriazinyl, 1,2, 4-benzotriazinyl, furopyridyl (such as furo [2,3-c ] pyridyl, furo [3,2-b ] pyridyl ] or furo [2,3-b ] pyridyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3, 4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
Halogen means the atoms fluorine, chlorine, bromine and iodine.
The designation of "halo" (e.g., as exemplified in the term haloalkyl) refers to the full degree of substitution from mono-to perhalo (e.g., as exemplified with methyl, such as chloromethyl (-CH)2Cl), dichloromethyl (-CHCl)2) Trichloromethyl (-CCl)3))。Anthelmintic compounds of the invention
In a first aspect of the invention, anthelmintic compounds of formula (I) are provided
Figure BDA0001193146030000141
Wherein:
X2or X7At least one of linker L19, L20 or L21 or a spirocyclic carbocyclic linker, a heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound to one carbon, wherein each ring of said spirocyclic linker comprises 4,5 or 6 ring atoms, and wherein L19, L20 or L21 or a spirocyclic ring linker are each optionally independently substituted with one or more of the following groups: halogen, cyano, C1-C6Alkyl radical, C1-6Haloalkyl, hydroxy, thiol, C1-6Alkoxy radical, C1-C6Haloalkoxy or oxo; y and Z are independently a bicyclic carbocyclic or heterocyclic group, optionally independently substituted with one or more of the following: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylaminoDialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkyl-or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl; or
One of Y or Z is a bicyclic carbocyclic or heterocyclic group, optionally substituted with one or more of the following: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkyl-or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl; and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl;
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl groups are optionally independently substituted with one or more substituents independently selected from the group consisting of: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkyl-or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl and heteroarylalkylsulfonyl;
X1is a bond, -O-, -C (O) -, -C (S) -, -NH-, -S (O) -, -S (O)2-,-NHS(O)-、 -S(O)-NH-、-NHSO2-、-SO2NH-、-(CH2)n- (wherein n is 1 to 3), -C (O) -CH2-、 -CH2-C(O)-、-O-CH2-、-CH2-O-、-NHCH2-、-CH2-NH-、-S-CH2-、-CH2-S-、 -S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-or-CH2-S(O)2-, each of NH-, -NH S (O) -, -S (O) -NH-, -NHSO2-、-SO2NH-、-(CH2)n、-C(O)CH2-、-CH2-C(O)-、-O-CH2-、-CH2-O、-NH-CH2、-CH2-NH-、-S-CH2-、-CH2-S-、 -S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2-the groups are optionally independently substituted with: oxo (═ O) or one or more halogen, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl or aryl groups, each of which is substitutedThe groups may be further substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH);
X2is a linking group selected from C1-C8Alkylene radical, C2-C8-alkenylene radical, C2-C8-an alkynylene group, a 3-8 membered carbocyclylene group and a 3-8 membered heterocyclylene group or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic-heterocyclic ring system bound to one carbon, wherein each ring of the spirocyclic ring system comprises 4,5 or 6 ring atoms, wherein the heterocyclylene group comprises one to four nitrogen, oxygen or sulfur atoms, and wherein said C is1-C8Alkylene radical, C2-C8-alkenylene group and C2-C8-one to three carbon atoms of the alkynylene group may be substituted by nitrogen, oxygen or sulfur atoms; and wherein said C1-C8Alkylene radical, C2-C8-alkenylene radical, C2-C8-an alkynylene group, a 3-8 membered carbocyclylene group, a 3-8 membered heterocyclylene group or a spirocyclic linker group is optionally independently substituted with one or more substituents independently selected from: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyl or arylsulfinyl, alkyl or arylsulfonyl and oxo (═ O);
X3is a diradical radical selected from the group consisting of a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -C (S) -, -C (O) -, -S (O)2And oxetane groups (4-membered rings containing one oxygen), in which X2And X4Any carbon atom that can be bonded to an oxetane group; and wherein- (CH)2)nEach of-CH in-group2-optionally independently substituted with one or two substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkeneA group, an alkynyl group, a haloalkynyl group, a carbocyclyl group and a halogenated carbocyclyl group;
X4is a bond, - (CH)2)n- (wherein n is 1 to 3), carbocyclylene or heterocyclylene, wherein said-CH2-, carbocyclylene and heterocyclylene groups are optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkylaminoalkyl, dialkylaminoalkyl, alkyl or arylsulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, and halocarbocyclyl;
X5is absent or is a bond, - (CH)2) n (wherein n is 1 to 3), carbocyclylene or heterocyclylene, wherein said- (CH)2) n, each-CH of carbocyclylene or heterocyclylene2-optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkylaminoalkyl, dialkylaminoalkyl, alkyl or arylsulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, and halocarbocyclyl;
X6is- (CH)2)n- (wherein n is 1 to 3), -O-, -C (O) -, -C (S) -, -S-, -S (O) -, -S (O)2-, -NH-, -C (O) -NH-, -C (S) -NH-, -NH-C (O) -NH-, -NH-C (S) -wherein (CH)2)neach-CH of the groups, -NH-, -C (O) -NH-, -C (S) -NH-, -NH-C (O) -, -NH-C (S) -2-optionally independently substituted with one or two substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkylaminoalkyl, dialkylaminoalkyl, alkyl or arylsulfinyl, alkyl or arylsulfonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, carbocyclylalkyl and halocarbocyclylalkyl;
X7is a bond, - (CH)2) n- (wherein n is 1 to 8), C2-C6-alkenylene, C2-C6-alkynylene, 3-8 membered carbocyclylene, 3-8 membered heterocyclylene containing 1 to 4 nitrogen, oxygen or sulfur atoms or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic ring system contains 4,5 or 6 ring atoms, wherein- (CH) is2)nCH in (E)2、C2-C6-alkenylene, C2-C6-alkynylene, 3-8 membered carbocyclylene, 3-8 membered heterocyclylene or spiro linker groups are each optionally independently substituted with one or more of the following: a halogen, hydroxy, hydroxyalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyl or arylsulfinyl, alkyl or arylsulfonyl or oxo (═ O) group; and
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent group may be further substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In one embodiment, at least one of Y or Z is an optionally substituted bicyclic carbocyclic group. In another embodiment, at least one of Y or Z is an optionally substituted bicyclic aromatic carbocyclic group. In yet another embodiment, at least one of Y or Z is an optionally substituted non-aromatic bicyclic carbocyclic group. In yet another embodiment, at least one of Y or Z is optionally substituted naphthyl, tetrahydronaphthyl, or indanyl.
In yet another embodiment, at least one of Y or Z is a bicyclic heterocyclic group. In another embodiment, at least one of Y or Z is an optionally substituted bicyclic heteroaryl group. In yet another embodiment, at least one of Y or Z is an optionally substituted indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl (benzodioxolyl), benzothienyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo [2,3-c ] pyridinyl, furo [3,2-b ] pyridinyl ] or furo [2,3-b ] pyridinyl), dihydroisoindolyl or dihydroquinazolinyl (such as 3, 4-dihydro-4-oxo-quinazolinyl).
In one embodiment, X1Is a bond, -C (O) -, -CH2-、-CH2CH2-、-C(O)-CH2-、 -CH2-C(O)、-O-CH2-、-CH2-O-、-NHCH2-or-CH2-NH-, wherein each-CH2-、 -CH2CH2-、-C(O)CH2-、-CH2-C(O)-、-O-CH2-、-CH2-O、-NH-CH2、-CH2-NH-is optionally independently substituted with one or more halogen, alkyl, haloalkyl or cycloalkyl groups.
In another embodiment, X1is-NH-, -NHS (O) -, -S (O) -NH-, -NHSO2-or-SO2NH-。
In another embodiment, X1Is a bond, -CH2-or-CH2CH2-, each of which is-CH2-or-CH2CH2-optionally independently of one another orA plurality of halogen, alkyl or haloalkyl groups.
In one embodiment, X1is-NH-optionally independently substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In one embodiment, X1is-NH-optionally independently substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, or haloalkyl, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In one embodiment of the invention, when X1Where the moiety is a nitrogen-containing group, it may be used to attach a group that will be converted in vivo to an unsubstituted-NH-group (e.g., a prodrug). Thus, in one embodiment, the invention includes the following compounds: wherein X1Is N (CH)2)qOR、 N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis-or trans-N (C ═ O) - ═ COOR, N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In one embodiment, X2Is C1-C8-an alkylene group, a 3-8 membered carbocyclylene group, a 3-8 membered heterocyclylene group containing 1 to 4 heteroatoms of nitrogen, oxygen or sulfur atoms, or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a spirocyclic carbocyclic-heterocyclic ring system bound to one carbon, wherein each ring of said spirocyclic ring system contains 4,5 or 6 ringsA ring atom, wherein said C1-C8-one or more carbon atoms of the alkylene group may be substituted by nitrogen, oxygen or sulfur atoms; and wherein said C1-C8-the alkylene group, 3-8 membered carbocyclylene group, 3-8 membered heterocyclylene group or spiro linker group is optionally independently substituted with one or more substituents selected from: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl and oxo (═ O).
In a preferred embodiment, X2is-C (═ O) -or optionally substituted C1-C3-An alkylene group.
In another embodiment, X2Comprises mixing X1Bridge to X3A chain of 3 to 6 atoms (in an acyclic chain or part of a ring), wherein 1 or 2 chain atoms are nitrogen. In this embodiment, X2The nitrogen atom in (1) is usually bonded to X1And/or X3。
In yet another embodiment, X2Comprises mixing X1Bridge to X3A chain of 3 to 6 atoms (in an acyclic chain or part of a ring), wherein 1 or 2 chain atoms are nitrogen, and wherein one or more alkylene groups of the chain are substituted by oxo (═ O).
In another embodiment, X2Is a 3-8 membered heterocyclylene group containing at least one nitrogen atom. In yet another embodiment, X2Is a heterocyclylene group containing at least two nitrogen atoms. In yet another embodiment, X2Is a 5-or 6-membered heterocyclylene group containing one or two nitrogen atoms.
In one embodiment, X2Is a 3 or 4-membered heterocyclylene linker having one ring nitrogen atom. In another embodiment, X2Is a 5 or 6-membered heterocyclylene linker having one or two ring nitrogen atoms. In yet another embodiment, X2Is a bicyclic heterocyclylene linker containing one or two nitrogen atoms, wherein each ring of the bicyclic ring system has 4,5, or 6 ring atoms.
In another embodiment, X2Is a spirocyclic carbocyclic linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a homo-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic ring system contains 4,5 or 6 ring atoms.
In certain preferred embodiments, X2And/or X7One selected from the group consisting of linking groups L1 through L21 in table 1 below, wherein the variables R and R' are each independently hydrogen, alkyl, haloalkyl, or arylalkyl; r2And R3Independently hydrogen, halogen, cyano, alkyl, haloalkyl or carbocyclyl; r4Is H, OH, halogen or C1-3An alkyl group; r5、R6、R7And R8Independently of one another is hydrogen, C1-3Alkyl or C1-3A haloalkyl group; w and W' are each independently O or S; and each linker group L1 to L21 in the table may be independently substituted with one or more halogen, cyano, C1-C6Alkyl, hydroxy, thiol, C1-C6Alkoxy, oxo or thiocarbonyl.
Examples of the linkers X2 and X7 in Table 1
Figure BDA0001193146030000211
It should be understood that X is present in Table 12And X7The linking group may be bonded to X at any possible atom in the linking group1And/or X3Or X6And/or X8. Generally, when X2And/or X7When the linker comprises one or more nitrogen atoms, said nitrogen atoms will be bonded to X1And/or X3Or X6And/or X8。
In one embodiment, X2And/or X7Is L1. In another preferred embodiment, X2And/or X7Is L2. In yet another preferred embodiment, X2And/or X7Is L11 or L12. In another embodiment, X2And/or X7Is L13 or L14. In yet another embodiment, X2And/or X7Is L13, wherein R is6And R7The groups are in trans relationship to each other. In yet another embodiment, X2And/or X7Is L13, wherein R6And R7The groups are in cis relationship to each other. In another embodiment, X2And/or X7Is L14, wherein R6And R7The groups are in trans relationship to each other. In yet another embodiment, X2And/or X7Is L14, wherein R6And R7In cis relationship to each other. In yet another embodiment, X2And/or X7Is L15, wherein R6And R7Are in trans to each other. In yet another embodiment, X2And/or X7Is L15, wherein R6And R7Are in cis to each other. In yet another embodiment, X2And/or X7Is L16, L17 or L18. In another embodiment, X2And/or X7Is L19, L20 or L21.
In some embodiments, X3Is a bond, - (CH)2)n- (wherein n is 1 to 3), -C (S) -or-C (O) -, wherein said- (CH)2) Each carbon atom in the n-group is optionally independently substituted with one or two substituents selected from halogen, alkyl, or haloalkyl. In a preferred embodiment, X3is-C (O) -. In another preferred embodiment, X3is-CH2CH2-or-CH2CH2CH2-wherein each carbon atom may be substituted by one or two methyl groups. In yet another embodiment, X3Is an oxetane group.
In one embodiment, X4Is a bond. In another embodiment, X4Is- (CH)2)n-, where n is 1 or 2, each-CH2-optionally substituted independently with one or two substituents selected from halogen, alkyl, haloalkyl and carbocyclyl;
in another embodiment, X5Is a bond or- (CH)2)n-, wherein n is 1 or 2 and wherein- (CH)2)neach-CH of the group2-optionally independently substituted with one or two halogen, alkyl, haloalkyl or carbocyclyl groups;
in still another embodiment of formula (I), X6Is- (CH)2)n(wherein n is 1 or 2), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-or-NH-, wherein- (CH)2)neach-CH of the group2-or NH is optionally independently substituted with one or two substituents selected from the group consisting of halo, alkyl, haloalkyl, and carbocyclyl. In a preferred embodiment, X6Is CH2. In another preferred embodiment, X6is-O-.
In another embodiment of formula (I), X7Is a bond, - (CH)2)n- (wherein n is 1 to 3), carbocyclylene or heterocyclylene, wherein- (CH)2)nCH in (E)2Carbocyclylene and heterocyclylene are each optionally independently substituted with one or more halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amino, alkylamino or dialkylamino groups or aminoalkyl groups. In another embodiment, X7Is a 5-or 6-membered carbocyclylene group, such as cyclohexylene or cyclopentylene. In yet another embodiment, X7Is a phenylene group.
In one embodiment, X7Is a 3 or 4-membered heterocyclylene linker having one ring nitrogen atom. In another embodiment, X7Is a 5 or 6-membered heterocyclylene linker having one or two ring nitrogen atoms. In yet another embodiment, X7Is a bicyclic heterocyclylene linker containing one or two nitrogen atoms, wherein each ring of the bicyclic ring system has 4,5, or 6 ring atoms. In another embodiment, X7Is a spirocyclic carbocyclic linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a homo-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic ring system contains 4,5 or 6 ring atoms.
In one embodiment of formula (I), X8Is absent or is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -or-NH-, wherein- (CH)2)nCH in (E)2and-NH-are each optionally independently substituted with one or two substituents selected from halogen, alkyl, and haloalkyl. In a particularly preferred embodiment, X8is-NH-. In another embodiment, X8is-C (O) -. In yet another preferred embodiment, X8is-CH2-、-CF2-、 -CH(CH3) -or-C (CH)3)2-. In yet another embodiment, X8is-NHS (O) -, -S (O) -NH-, -NHSO2-or-SO2NH-。
In another embodiment, X8is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In one embodiment, X8is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein the substituents may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In another embodiment of the present invention, when X8Where the moiety is a nitrogen-containing group, it may be used to attach a group that will be converted in vivo to an unsubstituted-NH-group (e.g., a prodrug). Thus, in one embodiment, the invention includes the following compounds: wherein X8Is N (CH)2)qOR、N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis or trans N (C ═ O) - ═ -COOR, N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In one aspect of the invention, the compounds of formula (I) have the structure (IA) shown below:
Figure BDA0001193146030000241
wherein variable Y, X1、X8And Z is as defined above for formula (I), ring A and ring B are independently a 3-to 8-membered monocyclic or 7-to 11-membered bicyclic carbocyclylene or heterocyclylene ring, or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic linker comprising two heterocyclic ring systems or a homo-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic ring system contains 4,5 or 6 ring atoms, wherein said C is1-C8-one or more carbon atoms in the alkylene group may be substituted by nitrogen, oxygen or sulfur atoms, wherein the heterocyclic ring contains 1 to 4 heteroatoms selected from N, O and S; and the linker is fragment-X3-X4-X5-X6-, wherein X3、X4、X5And X6As defined for formula (I).
In one embodiment of formula (IA), ring a is one of L1 to L10, L13 to L18, or L19 to L21 as defined in table 1, which may be optionally substituted with halogen, alkyl or haloalkyl. In another embodiment, ring a is cyclohexylene or phenylene, which may be optionally substituted with halogen, alkyl, or haloalkyl. In another embodiment of formula (IA), ring B is cyclohexylene or phenylene, which may be optionally substituted with halogen, alkyl or haloalkyl. In yet another embodiment, ring B is one of L1 to L10, L13L 18, or L19 to L21 as defined in table 1, which may be optionally substituted with halogen, alkyl, or haloalkyl.
In one embodiment of formula (IA), X1Is a bond, optionally substituted- (C)H2)n- (wherein n is 1 to 3), or-C (O) -.
In another embodiment of formula (IA), X8is-C (O) -, -NH-or- (CH)2)n- (wherein n is 1 to 3) wherein- (CH)2)nCH in (E)2or-NH-may each be optionally substituted.
In yet another embodiment of formula (IA), Y and/or Z is phenyl or naphthyl optionally substituted with one or more of the following groups: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl, with the proviso that at least one of Y or Z is naphthyl.
In yet another embodiment of formula (IA), Y and/or Z are independently phenyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring.
In some embodiments of formula (IA), the compound has the structure of formula (IA-1) or (IA-2) as shown below:
Figure BDA0001193146030000251
Figure BDA0001193146030000261
wherein variable Y, X1、X6、X8And Z is as defined for formula (I) above; ring A is a 3-to 8-membered or 5-to 6-membered carbocyclic or heterocyclic ring, wherein Q5And Q6Independently N, C or CR4Wherein R is4Is H, OH, halogen or C1-3An alkyl group; each Q4Is ring nitrogen, oxygen or sulfur or a substituent R1(ii) a W is O, S or an oxetane group (-CH)2OCH2-) according to the formula (I); ring B is a 3-to 8-membered monocyclic carbocyclic or heterocyclic ring, a 7-12 membered bicyclic carbocyclic or heterocyclic ring, or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring system comprising two heterocyclic rings or carbocyclic-heterocyclic ring systems bound at one carbon, wherein each ring of said spirocyclic linker comprises 4,5 or 6 ring atoms; wherein Q1And Q2Independently N, C or CR4Wherein R is4Is H, OH, halogen or C1-3An alkyl group; each Q3Is ring nitrogen, oxygen or sulfur or a substituent R1(ii) a Each R1Independently hydrogen, halogen, cyano, hydroxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, carbocyclyl, heterocyclyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; r2And R3Independently hydrogen, halogen, cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1,2 or 3; m is 0, 1,2,3 or 4; and q is 0, 1,2,3 or 4, with the proviso that ring a and ring B do not contain more than 4 ring heteroatoms, and wherein the rings may be fully saturatedAnd, partially saturated or fully saturated, provided that at least one of ring a or ring B is one of L19, L20, or L21 shown in table 1 or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system that bind one carbon, wherein each ring of said spirocyclic linker comprises 4,5, or 6 ring atoms.
In one embodiment of formula (IA-1), W is O. In another embodiment, W is an oxetane group. In another embodiment, ring B is optionally substituted phenylene.
In another embodiment of formula (IA-1) or (IA-2), ring a is a linker L1, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20 or L21. In another embodiment, ring a is one of L1, L13, L14, or L15. In yet another embodiment, ring a is L16, L17, or L18. In yet another embodiment, ring a is L19, L20, or L21. In another embodiment, ring a is L4, L5, L6, L7, L9, or L10. In another embodiment, ring B is L1, L13, L14, or L15. In another embodiment, ring B is L19, L20, or L21.
In another embodiment, ring a and ring B are each independently one of L1, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21.
In still another embodiment of formula (IA-1), Y and/or Z is naphthyl optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IA-1), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment of formula (IA-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl, a 3-to 8-membered heterocyclyl group or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IA-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl or a 5-or 6-membered heteroaryl group, optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment, one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is phenyl, optionally substituted by cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl substitution.
In another embodiment, X1is-NH-, -NHS (O) -, -S (O) -NH-, -NHSO2-or-SO2NH-。
In another embodiment, X1Is a bond, -CH2-or-CH2CH2-, each of which is-CH2-or-CH2CH2-optionally independently substituted with one or more halogen, alkyl or haloalkyl groups.
In one embodiment, X1is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl groups, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxyA group (-COOH).
In another embodiment, X1is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In one embodiment, X1Is N (CH)2)qOR、N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis-or trans-N (C ═ O) - (COOR) or N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In one embodiment, X8is-NH-, -NHS (O) -, -S (O) -NH-, -NHSO2-or-SO2NH-。
In another embodiment, X8Is a bond, -CH2-or-CH2CH2-, each of which is-CH2-or-CH2CH2-optionally substituted with one or more halogen, alkyl or haloalkyl groups.
In yet another embodiment, X8is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In yet another embodiment, X8is-NH-optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkylAlkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, wherein each substituent group may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In one embodiment, X8Is N (CH)2)qOR、N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis-or trans-N (C ═ O) - (COOR) or N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In another embodiment, X1Is optionally substituted- (CH)2)n-or-C (O) -. In another embodiment, X8is-C (O) -or optionally substituted-NH-or- (CH)2)n-. In still another embodiment of formula (IA-1), R2And R3Is H. In another embodiment, R2And R3One or two of (a) is methyl. In still another embodiment of formula (IA-1), n is 1 or 2.
In another embodiment of formula (IA-1), X6is-O-, -NH-which may be optionally substituted by alkyl or haloalkyl; -S-, -S (O) -or-S (O)2-。
In still another embodiment of formula (IA-1), X1Is a bond, -C (O) -or-CH2-; w is O, X6is-O-, n is 0, 1 or 2, R2And R3Are both H and m and q are 0.
In one embodiment of formula (IA-1), Q3Is a ring nitrogen and q is 1. In another embodiment, Q3Is a ring nitrogen and q is 2. In another embodiment, Q4Is a ring nitrogen and m is 1. In yet another embodiment, Q4Is a ring nitrogen and m is 2.
In one embodiment, Q2And Q5Is N. In another embodiment, Q5And Q6Is N and Q1And Q2Are both C or CH.
In another embodiment of formula (IA-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl-or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Halogenoalkoxy, C1-3Alkylthio, halogenothio, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
ring a is one of L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20, or L21 shown in table 1;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NHCH2-、 -S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2In which is- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more halo, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Aminoalkyl radical, C1-3Alkyl and C1-3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3Alkyl radical, C1-3Haloalkyl and C1-3An alkoxyamino group;
Q1and Q2Each independently is C-H or N;
Q3is C-H or a ring nitrogen;
n is 0, 1,2 or 3; and q is 0, 1 or 2.
In another embodiment of formula (IA-1), ring a is one of L19, L20, or L21; ring B is optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that Y or Z is up toAt least one is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O or an oxetane group, X6is-O-, n is 0, 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a is optionally substituted cyclohexylene or phenylene and ring B is one of L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is naphthyl optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O or an oxetane group, X6is-O-, n is 0, 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a and ring B are each independently one of L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halogenothioA group, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl group, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O or an oxetane group, X6is-O-, n is 0, 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、 -CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a is one of L19, L20, or L21; ring B is an optionally substituted diradical pyridine ring linker wherein Q3Is a ring nitrogen, Q1And Q2Is C and q is 1, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O or an oxetane group, X6is-O-, n is 0, 1 or 2, R2And R3Is H, m is 0 and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring A is an optionally substituted bistidyl ring linker wherein Q4Is a ring nitrogen, Q5And Q6Is C and m is 1, ring B is one of L19, L20 or L21; y and/or Z are independently phenyl, naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, each of which is optionally independently substituted by oneOr a plurality of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O or an oxetane group, X6is-O-, n is 0, 1 or 2, R2And R3Is H, q is 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a is L19, L20, or L21; ring B is optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a and ring B are each independently one of L1, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl,A benzoxazolyl or benzothiazolyl group, each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a is optionally substituted cyclohexylene or phenylene and ring B is L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond, -C (O) -or-CH2-; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IA-1), ring a is L19, L20, or L21; ring B is optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolylOr benzothiazolyl, each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is NH-, optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8Is a bond.
In another embodiment of formula (IA-1), ring a is L19, L20, or L21; ring B is optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8Is NH-, optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl and haloalkyl, wherein each substituent may be further independently replaced by hydroxy, hydroxyalkyl, amino, alkylAlkylamino, dialkylamino or carboxy (-COOH).
In another embodiment of formula (IA-1), ring a is L19, L20, or L21, ring B is optionally substituted cyclohexylene or phenylene, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is naphthyl optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is NH-, wherein hydrogen is optionally substituted with a substituent selected from the group consisting of: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0 and X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In another embodiment of formula (IA-1), ring a and ring B are each independently one of L1, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl,each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8Is a bond.
In another embodiment of formula (IA-1), ring a and ring B are each independently one of L1, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, each of which is takenThe substituents may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In another embodiment of formula (IA-1), ring a and ring B are each independently one of L1, L2, L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0 and X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In another embodiment of formula (IA-1), ring A is optionally substituted cyclohexylene or phenylene; ring B is L19, L20 or L21; y and/or Z are independently phenyl, naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranylA benzimidazolyl, benzoxazolyl or benzothiazolyl group, each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8Is a bond.
In another embodiment of formula (IA-1), ring A is optionally substituted cyclohexylene or phenylene; ring B is L19, L20 or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1Is a bond; w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, each of which is takenThe substituents may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In another embodiment of formula (IA-1), ring A is optionally substituted cyclohexylene or phenylene; ring B is L19, L20 or L21; y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x1is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH); w is O, X6is-O-, n is 1 or 2, R2And R3Is H, m and q are 0 and X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In another embodiment of formula (IA-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, cyano, nitro, or nitro,Bromine, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
ring a is one of L19, L20 or L21;
ring B is trans-cyclohexylene or phenylene;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein- (CH)2) CH in n-2and-NH-is each optionally independently substituted with one or two groups selected from: halogen, C1-3Alkyl radical, C1-3Haloalkyl, hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl and C2-4Alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; n is 1 or 2; and m and q are 0.
In another embodiment of formula (IA-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3) or-NH-, wherein- (CH)2)nCH in (E)2and-NH-is each optionally independently substituted with one or two groups selected from: halogen, C1-3Alkyl radical, C1-3Haloalkyl, hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl and C2-4Alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
ring a is trans-cyclohexylene or phenylene;
ring B is one of L19, L20 or L21;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein- (CH)2)nCH in (E)2and-NH-is each optionally independently substituted with one or two groups selected from: halogen, C1-3Alkyl radical, C1-3Haloalkyl, hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl and C2-4Alkenylcarbonyl, each of which may be further substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxyl (-COOH) substitution；
R2And R3Is H; n is 1 or 2; and m and q are 0.
In still another embodiment of formula (IA-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3) or-NH-, wherein- (CH)2)nCH in (E)2and-NH-is each optionally independently substituted with one or two groups selected from: halogen, C1-3Alkyl radical, C1-3Haloalkyl, hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl and C2-4Alkenylcarbonyl, each of which may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
ring a and ring B are each independently one of L1, L2, L3, L4, L5, L13, L14, L15, L16, L17, L18, L19, L20, or L21;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein- (CH)2)nCH in (E)2and-NH-is each optionally independently substituted with one or two groups selected from: halogen, C1-3Alkyl radical, C1-3Haloalkyl, hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl and C2-4Alkenylcarbonyl, each of which may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; n is 1 or 2; and m and q are 0.
In other embodiments, the present invention provides compounds of formula (IA-1) shown in Table 2 below, wherein W is O; r2And R3Is H; n is 1 and the variable Y, X1、X6、X8Z and Ring A and Ring B (which includes the variable Q)1、Q2、Q3、Q4、Q5、Q6M and q) are described as
Figure BDA0001193146030000411
TABLE 2 Compounds of formula (IA-1) wherein W is O; r2And R3Is H; n is 1; and B represents a bond.
Figure BDA0001193146030000421
Figure BDA0001193146030000431
Figure BDA0001193146030000441
Figure BDA0001193146030000451
Figure BDA0001193146030000461
Figure BDA0001193146030000471
The present invention provides a compound of (IA-2), wherein at least one of ring a or ring B is L19, L20, or L21, or a spirocyclic carbocyclic linker, a heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic linker comprises 4,5, or 6 ring atoms.
In one embodiment of formula (IA-2), W is O. In another embodiment, W is an oxetane group.
In another embodiment of formula (IA-2), ring a is one of the linkers L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21. In another embodiment, ring a is one of L1, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21. In another embodiment, ring a is L1, L13, L14, or L15. In yet another embodiment, ring a is L16, L17, L18, L19, L20, or L21. In yet another embodiment, ring a is L19, L20, or L21.
In another embodiment of formula (IA-2), ring B is one of the linkers L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20 or L21. In another embodiment, ring B is one of L1, L2, L3, L8, L13, L14, L15, L16, L17, L18, L19, L20, or L21. In another embodiment, ring B is L1, L13, L14, or L15. In yet another embodiment, ring B is L16, L17, L18, L19, L20, or L21. In another embodiment, ring B is L19, L20, or L21.
In still another embodiment of formula (IA-2), Y and/or Z is naphthyl independently substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IA-2), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment of formula (IA-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl, a 3-to 7-membered heterocyclyl group or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IA-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl or a 5-or 6-membered heteroaryl group, optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment, one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: chlorine, fluorine, bromine, CF3、OCF3、SCF3Or SF5(ii) a And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
in another embodiment of formula (IA-2), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, and indolylImidazolyl, benzoxazolyl and benzothiazolyl, each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl-or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Halogenoalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl radical, C1-3Haloalkylsulfonyl or SF5Provided that at least one of Y and Z is a bicyclic ring;
ring a is one of linkers L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17, L18, L19, L20, or L21;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NHCH2-、 -S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-、-CH2-S(O)2-and-NH-, wherein- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-、-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and-NH-is optionally substituted with: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, wherein each substituent on-NH-may be further independently substituted with a hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH) group;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, and alkoxyalkyl; n is 0, 1,2 or 3; and m and q are independently 0, 1,2,3 or 4.
In one embodiment, X1is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, wherein each substituent may be further substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In one embodiment, X1Is N (CH)2)qOR、N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis-or trans-N (C ═ O) - ═ COOR, N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In one embodiment, X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl,dialkylamino or carboxyl (-COOH) groups.
In another embodiment, X8Is N (CH)2)qOR、N(CH2)qNR2、N(CH2)qO(CH2)qOH, cis-or trans-N (C ═ O) - ═ COOR, N (C ═ O) (CH)2)qCOOR, wherein R is hydrogen or C1-C6-alkyl and q is an integer selected from 1,2,3 or 4.
In another embodiment, X1Is optionally substituted- (CH)2)n-or-C (O) -. In another embodiment, X8is-C (O) -or optionally substituted-NH-or- (CH)2)n-. In still another embodiment of formula (IA-2), R2And R3Is H. In still another embodiment of formula (IA-2), n is 1 or 2. In still another embodiment of formula (IA-2), X1Is a bond, -C (O) -or-CH2-; w is O, n is 1 or 2, R2And R3Are both H and m and q are 0.
In another embodiment of formula (IA-2), Y and/or Z are independently naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl; x1Is a bond, -C (O) -or-CH2-; w is O, n is 1 or 2, R2And R3Is H, m and q are 0, and X8is-NH-, -C (O) -, -CH2-、 -CF2-、-CH(CH3) -or-C (CH)3)2-。
In other embodiments, the present invention provides compounds of formula (IA-2) in Table 3 below, wherein Y, X1、R2、R3、n、W、X8Z and Ring A and Ring B (which includes the variable Q)1、Q2、Q3、 Q4、Q5、Q6M and q):
Figure BDA0001193146030000521
TABLE 3 Compounds of formula (IA-2)
Figure BDA0001193146030000522
In another aspect of the invention, the compound of formula (I) has the structure (IB) shown below:
Figure BDA0001193146030000523
wherein variable Y, X8And Z is as defined for formula (I), ring B is independently a 3-to 8-membered carbocyclylene or heterocyclylene ring having 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; a 7-to 12-membered bicyclic carbocyclylene or heterocyclylene ring comprising 1 to 4 members selected from oxygen, sulfur and nitrogen; a spirocyclic heterocyclic ring comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic linker contains 4,5, or 6 ring atoms; or one of L1 to L10 or L13 to L21; and the linker is a fragment X1-X2-X3-X4-X5-X6-, wherein X1、X2、X3、X4、X5And X6As defined for formula (I).
In one embodiment of formula (IB), linker fragment X1-X2-X3-X4-X5-X6Variable X in (E)4And/or X5Is absent. In another embodiment of formula (IB), ring B is one of L19 through L21 as defined in table 1, which may be optionally substituted with halogen, alkyl, or haloalkyl. In yet another embodiment of formula (IB), Y and/or Z are optionally substituted with one or more groupsNaphthyl: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.
In yet another embodiment of formula (IB), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.
In another embodiment of formula (IB), the compound has the structure of formula (IB-1), (IB-2), (IB-3), or (IB-4) as shown below, wherein the ring is L19, L20, or L21 or a spirocyclic carbocyclic ring linker, one of spirocyclic heterocyclic ring linkers comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of the spirocyclic linker comprises 4,5, or 6 ringsEach of which may optionally be independently substituted with one to four R independently selected from1Substituent group substitution: halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl and haloalkynyl.
Figure BDA0001193146030000541
Y, X therein1、X6、X8And Z is as defined above for formula (I); w and W' are each independently O, S or an oxetane; q1And Q2Each independently is C-H or N; r and R' are each independently hydrogen, alkyl, haloalkyl or arylalkyl; r2And R3Independently hydrogen, halogen, cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1,2 or 3; wherein the ring may be fully saturated, partially saturated or fully saturated.
In one embodiment of formulae (IB-1), (IB-2), (IB-3) and (IB-4), Y and/or Z are naphthyl optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl. In still another embodiment of formulas (IB-1), (IB-2), (IB-3), and (IB-4), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment of formulas (IB-1), (IB-2), (IB-3), and (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl, a 3-to 8-membered heterocyclyl group or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In still another embodiment of formulas (IB-1), (IB-2), (IB-3), and (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl or a 5-or 6-membered heteroaryl group, optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment, one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl.
In one embodiment of formulae (IB-1), (IB-2), (IB-3) and (IB-4), Q1Is N. In another embodiment, Q2Is N.
In one embodiment of formula (IB-1), W is O. In another embodiment, W is an oxetane group. In yet another embodiment, the ring is an optionally substituted phenylene group. In yet another embodiment, X6is-NH-, in which hydrogen may be alkyl, haloalkyl or arylalkyl, -O-, -S-, -S (O) -or-S (O)2-substitution. In another embodiment, X6Is- (CH)2)n-optionally substituted by halogen, alkyl or haloalkyl. In still another embodiment of formula (IB-1), R2And R3Is H. In still another embodiment of formula (IB-1), n is 1 or 2. In another embodiment of formula (IB-1), X6is-O-or-NH-, which may be optionally substituted by alkyl or haloalkyl or arylalkyl.
In one embodiment, X8is-NH-, -NHS (O) -, -S (O) -NH-, -NHSO2-or-SO2NH-。
In another embodiment, X8Is a bond, -CH2-or-CH2CH2-2-or-CH2CH2-optionally independently substituted with one or more halogen, alkyl or haloalkyl groups.
In yet another embodiment, X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH).
In yet another embodiment, X8is-NH-wherein hydrogen is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, and haloalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, or carboxy (-COOH).
In one embodiment of formula (IB-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, SF5Alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -, in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are each optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl and haloalkyl;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl and alkoxyalkyl, wherein each substituent may be further independently substituted with: hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH);
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substitution; and
n is 0, 1,2 or 3.
In another embodiment of formula (IB-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, SF5、C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl-or C1-3DialkylaminesBase, C1-3Alkoxy radical, C1-3Halogenoalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -, in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are each optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Aminoalkyl radical, C1-3Alkyl and C1-3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxyalkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylaminoDialkylamino or carboxy (-COOH); and
n is 0, 1,2 or 3.
In still another embodiment of formula (IB-1), W is O, X6is-O-, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; n is 1 or 2, and R2And R3Is H.
In another embodiment of formula (IB-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is phenyl, optionally substituted by cyano, nitro, CF3、 SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl substitution;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substitution;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IB-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IB-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IB-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IB-1), the ring is optionally substituted with halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19; w is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl or benzothiazolyl, X6is-O-, n is 1 or 2, R2And R3Is H; and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IB-1), the ring is L20, W is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, X6is-O-, n is 1 or 2, R2And R3Is H; and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IB-1), the ring is L21, W is O, Y and/or Z are independently optionally substituted naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, X6is-O-, n is 1 or 2, R2And R3Is H; and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In one embodiment of formula (IB-2), W is O. In another embodiment, X1is-O-, -S-or-NH-wherein the hydrogen atom may be replaced by an alkyl, haloalkyl or arylalkyl group. In still another embodiment of formula (IB-2), X6is-NH-, wherein the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl; -O-, -S (O) -or-S (O)2-. In another embodiment, X6Is- (CH)2)nOptionally substituted by halogen, alkyl or haloalkyl. In still another embodiment of formula (IB-2), R2And R3Is H. In still another embodiment of formula (IB-2), n is 1 or 2.
In yet another embodiment of formula (IB-2), W is O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylAmino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; x6is-O-, X1And X8is-NH-, n is 1 or 2, and R2And R3Is H.
In another embodiment of formula (IB-2), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or SF5Provided that at least one of Y and Z is a bicyclic ring;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substituted L19, L20, or L21;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, aminoalkylcarbonyl, aminoalkyl,Alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
w is O, S or an oxetane group;
R2and R3Independently is H, halogen, alkyl or haloalkyl;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl and alkoxyalkyl, wherein each substituent may be further independently substituted with: hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (-COOH); and n is 0, 1,2 or 3.
In another embodiment of formula (IB-2), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl-or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Halogenoalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl radical, C1-3Haloalkylsulfonyl or SF5Provided that at least one of Y and Z is a bicyclic ring;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each optionally independently substituted with oxo (═ O) or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3-Alkyl, alkoxy-C1-3-Alkyl, amino-C1-3-Alkyl radical, C1-3alkylamino-C1-3-Alkyl radical, C1-3dialkylamino-C1-3-Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxyalkyl, wherein each substituent may be further independently by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3,SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl orC1-3Haloalkyl-substituted L21;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), the ring is optionally substituted with halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19; w is O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x6is-O-, X1is-NH-, n is 1 or 2, R2And R3Is H, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazoleOr benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w is O;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-2), the ring is L19, L20, or L21, W is O, Y and/or is independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x6is-O-, X1is-NH-, n is 1 or 2, R2And R3Is H, and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment, the present invention provides compounds of formulae (IB-1) and (IB-2) in Table 4 below, wherein Y, X1、W、n、R2、R3、X6、X8And a ring (which includes the variable Q)1And Q2) As described in the table.
TABLE 4 Compounds of formulae (IB-1) and (IB-2). Wherein X1Compounds which are bonds correspond to formula (IB-1).
Figure BDA0001193146030000671
Figure BDA0001193146030000672
Figure BDA0001193146030000681
Figure BDA0001193146030000691
Figure BDA0001193146030000701
In one embodiment of formula (IB-3), W and W' are each O. In still another embodiment of formula (IB-3), X6is-NH-, wherein hydrogen may be alkyl, haloalkyl or arylalkyl, -O-, -S-, -S (O), or-S (O)2-substitution. In another embodiment, X6Is- (CH)2)nOptionally substituted by halogen, alkyl or haloalkyl. In another embodiment of formula (IB-3), the ring is L19, L20, or L21, optionally substituted with one to four substituents independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, and haloalkynyl. In still another embodiment of formula (IB-3), R2And R3Is H. In still another embodiment of formula (IB-3), n is 1 or 2. In another embodiment of formula (IB-3), R and R' are each independently hydrogen or alkyl.
In another embodiment of formula (IB-3), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranA group, a quinolinyl group, an isoquinolinyl group, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, an indolyl group, an isoindolyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group, or a benzothiazolyl group, each of which is optionally independently substituted with one or more of the following groups: halogen, nitro, cyano, SF5、C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
w and W' are independently O, S or an oxetane group;
r and R' are independently H, C1-3Alkyl or C1-3A haloalkyl group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -, in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are each optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Aminoalkyl radical, C1-3Alkyl and C1-3A haloalkyl group;
X8is absent or is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2) CH in n-2、-NHS(O)-,-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-is each optionally independently substituted by one or twoSubstituted with one substituent selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxyalkyl, wherein each substituent may be further independently by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In still another embodiment of formula (IB-3), W and W' are O, X6is-O-or-NH-, n is 1 or 2, R2And R3Is H, Y and/or Z is independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring;
in another embodiment of formula (IB-3), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally substituted by a substituent selected from: hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-3), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, aryl, heteroaryl, and heteroaryl,S(O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally substituted by a substituent selected from: hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-3), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally substituted by a substituent selected from: hydroxy-C1-3Alkyl radical, C1-3alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-3), the ring is L19, L20, or L21, optionally substituted with halogen, C1-3Alkyl or C1-3Haloalkyl substitution; w and W' are O, Y and/or Z are independently optionally substituted phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, wherein at least one of Y or Z is a bicyclic ring; x6is-O-, n is 1 or 2, R2And R3Is H; r andr' is H or C1-3An alkyl group; and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IB-3), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3,SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substituted L19, L20, or L21;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally substituted by a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-3), the ring is L19, L20, or L21, optionally substituted with halogen, C1-3Alkyl or C1-3Haloalkyl substitution; w and W' are O, Y and/or Z are independently optionally substituted phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, wherein at least one of Y or Z is bicyclic; x6is-O-, n is 1 or 2, R2And R3Is H, and X8is-NH-, -C (O) -, -CH2-、 -CF2-、-CH(CH3) -or-C (CH)3)2-。
In one embodiment of formula (IB-4), W and W' are each O. In another embodiment, X1is-O-, -S-or-NH-, wherein the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl. In another embodiment, X8is-O-, -S-or-NH-, wherein a hydrogen atom may be replaced by an alkyl group, a haloalkyl group or an arylalkyl group. In still another embodiment of formula (IB-4), X6is-NH-, wherein the hydrogen may be replaced by alkyl, haloalkyl or arylalkyl; -O-, -S (O) -or-S (O)2-. In another embodiment, X6Is- (CH)2)nOptionally substituted by halogen, alkyl or haloalkyl. In another embodiment of formula (IB-4), the ring is L19. In yet another embodiment, the ring is L20 or L21. In another embodiment, X1Is- (CH)2)nOptionally substituted by halogen, alkyl or haloalkyl.
In still another embodiment of formula (IB-4), R2And R3Is H. In still another embodiment of formula (IB-4), n is 1 or 2. In another embodiment of formula (IB-4), R and R' are independently hydrogen or alkyl. In still another embodiment of formula (IB-4), W and W' are O, Y and/orZ is independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclic ring; x6is-O-or-NH-, n is 1 or 2, and R2And R3Is H.
In another embodiment of formula (IB-4), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, SF5Alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
w and W' are independently O, S or an oxetane group;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substituted L19, L20, or L21;
r and R' are independently H, alkyl or haloalkyl;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each optionally independently substituted with oxo (═ O) or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Independently is H, halogen, alkyl or haloalkyl;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -, in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are each optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl and haloalkyl;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloAlkynyls, carbocyclyls, heterocyclyls, carbocyclylalkyls, and heterocyclylalkyls, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In another embodiment of formula (IB-4), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, SF5、C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Halogenoalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
w and W' are independently O, S or an oxetane group;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl substituted L19, L20, or L21;
r and R' are independently H, C1-3Alkyl or C1-3A haloalkyl group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each optionally independently substituted with oxo (═ O) or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-, -NH-, -C (O) -NH-and-NH-C (O) -, in which- (CH)2)n-CH in the radical2-, -NH-, -C (O) -NH-and-NH-C (O) -are each optionally independently substituted with one or more substituents independently selected from: halogen, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3-dialkylamino-C1-3Alkyl radical, C1-3Alkyl and C1-3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Alkoxyalkyl group, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3-Alkyl radical, C1-3dialkylamino-C1-3-Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino orCarboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylAlkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5Is substituted and the other of Y or Z isOptionally substituted by cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring being optionally substituted by halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In yet another embodiment of formula (IB-4), the ring is L19 to L21, W and W' are O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is- (CH)2)n- (wherein n is 1 or 2), optionally substituted by halogen, alkyl or haloalkyl; x6is-O-, n is 1 or 2; r2And R3Is H; and X8is-NH-, -C (O) -, -CH2-、-CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring is L19;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, - (CH)2)n- (wherein n is 1 to 3), -NH-, wherein each- (CH)2)n-optionally independently substituted with one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (it)Wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), O or-NH-, wherein each- (CH)2)n-optionally independently substituted with one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring is L20;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, - (CH)2)n- (wherein n is 1 to 3), -NH-, wherein each- (CH)2)n-optionally substituted independently by the following groups or by one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), O or-NH-, wherein each- (CH)2)n-optionally substituted independently by the following groups or by one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In another embodiment of formula (IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3、SCF3Or SF5And the other of Y or Z is optionally cyano, nitro, CF3、SF5、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
the ring is L21;
w and W' are O;
r and R' are H or C1-3An alkyl group;
X1is a bond, - (CH)2)n- (wherein n is 1 to 3), -NH-, wherein each- (CH)2)n-optionally substituted independently with the following groups or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
X6is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), O or-NH-, wherein each- (CH)2)n-optionally substituted independently by the following groups or by one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
R2and R3Is H; and n is 1 or 2.
In yet another embodiment of formula (IB-4), the ring is L19, L20, or L21, W and W' are O, Y and/or Z are independently phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxyA hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl group, with the proviso that at least one of Y or Z is a bicyclic ring; x1Is- (CH)2)n- (wherein n is 1 or 2) optionally independently substituted by halogen, alkyl or haloalkyl; x6is-O-, n is 1 or 2; r2And R3Is H; and X8is-NH-, -C (O) -, -CH2-、-CF2-、 -CH(CH3) -or-C (CH)3)2-。
In another embodiment, the present invention provides compounds of formulae (IB-3) and (IB-4) in Table 5 below, wherein Y, X1、R、R'、X6、X8Z and the ring (including the variable Q)1And Q2) Described in the table, and W, W' is O, R2And R3Is H, and n is 2.
TABLE 5 Compounds of formulae (IB-3) and (IB-4), where W and W' are O, R2And R3Is H, and n is 2. Wherein X1Compound (B) as a bond corresponds to formula (IB-3):
Figure BDA0001193146030000871
Figure BDA0001193146030000872
Figure BDA0001193146030000881
Figure BDA0001193146030000891
in another aspect of the invention, the compound of formula (I) has the structure (IC) shown below:
Figure BDA0001193146030000892
wherein variable Y, X1And Z is as defined for formula (I), ring a is L19, L20, or L21 or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound to one carbon, wherein each ring of said spirocyclic linker contains 4,5, or 6 ring atoms, wherein L19, L20, L21, or spirocyclic ring linker are each optionally independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, and haloalkynyl; and the linker is fragment-X3-X4-X5-X6-X7-X8-, wherein X3、X4、X5、X6、X7And X8As defined for formula (I).
In one embodiment of formula (IC), Y and/or Z is naphthyl optionally substituted with one or more of the following groups: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.
In another embodiment of formula (IC), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.
In another embodiment of formula (IC), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl, a 3-to 7-membered heterocyclyl group or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IC), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl or a 5-or 6-membered heteroaryl group, optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment, one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: chlorine, fluorine, bromine, CF3、OCF3、SCF3A halothio group, and the other of Y or Z is optionally cyano, nitro, CF3、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
in one embodiment of formula (IC), the ring a is L19. In another embodiment, the ring a is L20. In yet another embodiment, the ring a is L21 as shown in table 1 above. In another embodiment, ring a is a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound at one carbon, wherein each ring of said spirocyclic linker comprises 4,5 or 6 ring atoms.
In one embodiment of formula (IC), the compound has the structure (IC-1) shown below:
Figure BDA0001193146030000921
y, X therein8And Z is as defined for formula (I) above; ring a is L19, L20 or L21 or a spirocyclic carbocyclic linker, a spirocyclic heterocyclic ring linker comprising two heterocyclic rings or a carbocyclic-heterocyclic ring system bound to one carbon, wherein each ring of said spirocyclic linker comprises 4,5 or 6 ring atoms, wherein L19, L20, L21 or said spirocyclic ring linker are each optionally independently substituted with one to four substituents selected from the group consisting of: halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl and haloalkynyl; q5And Q6Independently is N or CH; x1Is a bond, -C (O) -, -C (S) -, -NH-, -S (O) -, -S (O)2-、-(CH2)n- (wherein n is 1 to 3), -O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-or-CH2-S(O)2-, wherein-NH-, - (CH)2)n-、-O-CH2-、-NHCH2-、 -S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkylaryl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; w is O, S or oxetane; r2And R3Independently hydrogen, halogen, cyano, alkyl, haloalkyl or carbocyclyl; and n is 1,2 or 3.
In one embodiment of formula (IC-1), W is O. In one embodiment, ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl substituted L19. In another embodimentWherein ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl substituted L20. In yet another embodiment, ring a is optionally substituted with halo, C1-3Alkyl or C1-3Haloalkyl substituted L21.
In still another embodiment of formula (IC-1), Y and/or Z is naphthyl optionally substituted with one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In yet another embodiment of formula (IC-1), Y and/or Z are independently benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment of formula (IC-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl, a 3-to 8-membered heterocyclyl group or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In still another embodiment of formula (IC-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other of Y or Z is phenyl or a 5-or 6-membered heteroaryl group, which is optionally substituted by one or more of the following groups: halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.
In another embodiment, one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: chlorine, fluorine, bromine, CF3、OCF3Or SCF3And the other of Y or Z is optionally cyano, nitro, CF3、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl.
In another embodiment, X1Is optionally substituted- (CH)2)n-or-C (O) -. In another embodiment, X8is-C (O) -or optionally substituted-NH-or- (CH)2)n-. In still another embodiment of formula (IC-1), R2And R3Is H. In still another embodiment of formula (IC-1), n is 1 or 2. In still another embodiment of formula (IC-1), X1Is a bond, -C (O) -or-CH2-; w is O, n is 1 or 2, and R2And R3Is H.
In another embodiment, X1Is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、 -S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2-optionally substituted independently by oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
in another embodiment, X8Is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -O-CH2-、-NH-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、 -S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2-optionally substituted independently by oxo (═ O) or one or more of the following groups: halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups, and said-NH-is optionally substituted with a substituent selected from: hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, wherein each substituent may be further independently substituted with hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
in another embodiment of formula (IC-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -NH-, -O-CH2-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, -C1-3-alkyl, -C1-3-haloalkyl, -C3-8-a cycloalkyl or aryl group, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-is optionally independently substituted by one or two groups selected fromSubstituent group substitution: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Alkoxyalkyl group, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In another embodiment of formula (IC-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, each of which is optionally substituted with one or more of the following: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -NH-, -O-CH2-、 -NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2- (CH)2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, -C1-3-alkyl, -C1-3-haloalkyl, -C3-8-a cycloalkyl or aryl group, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxyRadical, amino radical, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Alkoxyalkyl group, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; q is 0, and n is 0, 1,2 or 3.
In another embodiment of formula (IC-1), Y and Z are independently phenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl, each of which is optionally independently substituted with one or more of the following: halogen, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, phenyl, hydroxy, C1-3Hydroxyalkyl, amino, C1-3Alkyl-or C1-3Dialkylamino radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylthio radical, C1-3Haloalkylthio, C1-3Alkylsulfinyl radical, C1-3Haloalkylsulfinyl radical, C1-3Alkylsulfonyl or C1-3Haloalkylsulfonyl, with the proviso that at least one of Y and Z is a bicyclic ring;
X1is a bond, -C (O) -, - (CH)2)n- (wherein n is 1 to 3), -NH-, -O-CH2-、 -NHCH2-、-S-CH2-、-S(O)-CH2、-CH2-S(O)-、-S(O)2-CH2-and-CH2-S(O)2-, wherein-(CH2)n-、-O-CH2-、-NHCH2-、-S-CH2-、-S(O)-CH2-、-CH2-S(O)-、 -S(O)2-CH2-and-CH2-S(O)2-each is optionally independently substituted with oxo (═ O) or one or more of the following groups: halogen, cyano, -C1-3-alkyl, -C1-3-haloalkyl, -C3-8-a cycloalkyl or aryl group, and said-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w is O, S or an oxetane group;
R2and R3Independently of one another H, halogen, C1-C3Alkyl or C1-C3A haloalkyl group;
X8is a bond, - (CH)2)n(wherein n is 1 to 3), -O-, -C (O) -, -S-, -S (O) -, -S (O)2-、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2NH-or-NH-, wherein- (CH)2)nCH in (E)2、-NHS(O)-、-S(O)-NH-、-NHSO2-、-SO2Each NH-or-NH-is optionally independently substituted with one or two substituents selected from: halogen, hydroxy, amino, C1-3Alkylamino radical, C1-3Dialkylamino radical, C1-3Hydroxyalkyl radical, C1-3Alkoxyalkyl group, C1-3Aminoalkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3-alkyl, wherein each substituent may further independently be replaced by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or carboxy (-COOH) substitution; and n is 0, 1,2 or 3.
In another embodiment of formula (IC-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3Or SCF3Substitution; and the other of Y or Z is optionally cyano, nitro, CF3,S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L19;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X1is a bond, -NH-, - (CH)2)n- (wherein n is 1 to 3) or-C (O) -;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally substituted by a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or Carboxy (COOH) substitution;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IC-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3Or SCF3And the other of Y or Z is optionally cyano, nitro, CF3、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L20;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X1is a bond, -NH-, - (CH)2)n- (wherein n is 1 to 3) or-C (O) -;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein the-NH-is optionally selected from the group consisting ofSubstituent group substitution: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or Carboxy (COOH) substitution;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IC-1), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of chloro, fluoro, bromo, CF3、OCF3Or SCF3Substitution; and the other of Y or Z is optionally cyano, nitro, CF3、S(O)C1-3Alkyl, S (O)2-C1-3Alkyl, S (O) C1-3Haloalkyl or S (O)2C1-3Haloalkyl-substituted phenyl;
ring A is optionally halogen, C1-3Alkyl or C1-3Haloalkyl-substituted L21;
w is O; x6Is a bond, -O-, - (CH)2)n- (wherein n is 1 to 3) or-NH-;
X1is a bond, -NH-, - (CH)2)n- (wherein n is 1 to 3) or-C (O) -;
X8is a bond, - (CH)2)n- (wherein n is 1 to 3), -O-or-NH-, wherein-NH-is optionally substituted with a substituent selected from: hydroxy-C1-3Alkyl, alkoxy-C1-3Alkyl, amino-C1-3Alkyl radical, C1-3alkylamino-C1-3Alkyl radical, C1-3dialkylamino-C1-3Alkyl radical, C1-3Alkoxycarbonyl group, C1-3Alkylcarbonyl group, C2-4Alkenylcarbonyl group, C1-3Alkyl radical, C1-3Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, carbocyclyl, heterocyclyl, carbocyclyl-C1-3Alkyl and heterocyclyl-C1-3Alkyl, wherein each substituent may be further independently substituted by hydroxy, hydroxy-C1-3Alkyl, amino, C1-3Alkylamino radical, C1-3Dialkylamino or Carboxy (COOH) substitution;
R2and R3Is H; and
n is 1 or 2.
In another embodiment of formula (IC-1), ring a is one of L19 to L21, Y and/or Z are independently naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, optionally substituted with one or more of the following: halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl-or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl; x1Is a bond, -C (O) -or-CH2-; w is O, n is 1 or 2, R2And R3Is H, and X8is-NH-, -C (O) -, -CH2-、 -CF2-、-CH(CH3) -or-C (CH)3)2-。
In another embodiment, the present invention provides compounds of formula (IC) in table 6 below:
TABLE 6 Compounds of formula (IC-1).
Figure BDA0001193146030001011
Figure BDA0001193146030001012
It was found that the compounds of the invention show higher permeability compared to the compounds of the prior art. For orally-administered compounds, the permeability of the compound across epithelial cells that follow the gastrointestinal tract is an important limiting factor for oral absorption and systemic availability of the compound. Thus, when administered orally or topically, the permeability of a systemically acting compound is one property that can significantly affect the efficacy of the compound against in vivo and/or in vitro parasites.
In one embodiment, the compounds of the present invention show surprisingly improved permeability compared to prior art compounds having only a single ring at the positions corresponding to Y and/or Z (e.g. the compounds of WO 2009/077527 and EP 2468096). The significantly higher permeability of the compounds of the present invention is expected to produce higher in vivo efficacy against endoparasites such as nematodes, as well as against ectoparasites that ingest blood (blood means) and/or colonize tissues such as the gastrointestinal mucosa. This is because an increased permeability through the mammalian intestinal tract increases the amount of active compound present in the blood circulation for delivery and uptake at the desired site. Furthermore, the increased permeability of the compound is likely to result in increased permeability across the nematode cuticle/adventitia. In addition, increased permeability of the active compound can result in improved transdermal access of the compound to the blood stream and/or tissue following topical administration.
In one embodiment, the compounds of the present invention exhibit a permeability of about 20% to about 30% higher than the compounds of the prior art. In another embodiment, the compounds of the present invention exhibit a permeability of from about 40% to about 60% or from about 50% to about 70% higher than compounds of the prior art. In still other embodiments, the compounds of the present invention exhibit a permeability of from about 60% to about 100%. In still other embodiments, the compounds of the present invention exhibit a permeability that is from about 20% to about 50% or from about 30% to about 75% higher than compounds of the prior art. In still other embodiments, the compounds of the present invention exhibit a permeability that is about 50% to about 100% higher than compounds of the prior art.
In other embodiments, the compounds of the present invention exhibit a permeability of about 50% to about 500% greater than compounds of the prior art. In other embodiments, the compounds of the present invention exhibit a permeability of about 100% to about 500% greater than compounds of the prior art. In still other embodiments, the compounds of the present invention exhibit a permeability of about 200% to about 400% greater than compounds of the prior art. In still other embodiments, the compounds of the present invention exhibit a permeability of from about 100% to about 300% greater or from about 200% to about 300% greater than compounds of the prior art. In still other embodiments, the compounds of the present invention exhibit a permeability of from about 100% to about 200% higher than compounds of the prior art. In other embodiments, the compounds of the present invention exhibit from about 300% to about 500% greater permeability or from about 400% to about 500% greater permeability as compared to compounds of the prior art.
Compositions of the invention
In another aspect, the present invention provides a parasiticidal composition comprising at least one anthelmintic compound of formula (I) of the present invention and a pharmaceutically acceptable carrier. The compositions of the present invention may also be in a variety of forms including, but not limited to, oral formulations, injectable formulations, and topical, dermal or subcutaneous formulations. The formulations are intended for administration to animals, including, but not limited to, mammals, birds, and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other domestic or domesticated mammals. Examples of birds include turkeys, chickens, ostriches, and other domestic or other domesticated birds.
The composition of the invention may also be in a form suitable for oral use, for example, as a bait (see, e.g., U.S. patent No.4,564,631, incorporated herein by reference), a dietary supplement, an aqueous lozenge, a troche, a chewable agent, a tablet, a hard or soft capsule, an emulsion, an aqueous or oily suspension, an aqueous or oily solution, an oral decoction, a dispersible powder or granule, a premix, a syrup or elixir, an enteric preparation or a paste. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc, which tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be produced by the methods described in U.S. patent nos. 4,256,108; 4,166,452; and 4,265,874 (incorporated herein by reference) to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules wherein the active ingredient is mixed with water or a water-miscible solvent such as propylene glycol, PEG and ethanol, or an oil medium such as peanut oil, liquid paraffin or olive oil.
The compositions of the invention may also be in the form of oil-in-water or water-in-oil emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or a mixture of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soya bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, bittering, flavoring and/or preservative agents.
In one embodiment of the formulation, the composition of the present invention is in the form of a microemulsion. Microemulsions are well suited for use as liquid carrier vehicles. Microemulsions are quaternary systems comprising a water phase, an oil phase, a surfactant, and a co-surfactant. They are translucent and isotropic liquids.
Microemulsions are composed as follows: a stable dispersion of droplets of an aqueous phase in an oil phase, or conversely a stable dispersion of droplets of an oil phase in an aqueous phase. The size of these droplets is less than 200nm (and 1000 to 100000nm for emulsions). The interfacial film is composed of alternating Surface Active (SA) and Co-surface active (Co-SA) molecules, which allow spontaneous microemulsion formation by lowering the interfacial tension.
In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of said compounds. In one embodiment of the oil phase, the oil phase comprises triglycerides; in another embodiment of the oil phase, the triglyceride is a medium chain triglyceride, e.g., C8-C10Caprylic/capric triglyceride. In another embodiment, the oil phase will comprise% v/v in a range selected from about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v microemulsion.
The aqueous phase comprises, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the diol derivative, the diol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Typically, the aqueous phase will be present in the microemulsion in a proportion of about 1 to about 4% v/v.
Surfactants for microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, pegylated C8-C10Glycerol or polyglycerol-6 dioleateAnd (3) an ester. In addition to these surfactants, co-surfactants include short chain alcohols such as ethanol and propanol.
Certain compounds are common to the three components discussed above, namely the aqueous phase, the surfactant and the co-surfactant. However, the level of skill of the practitioner is sufficient to use different compounds well for each component of the same formulation. In one embodiment of the amount of surfactant/co-surfactant, the ratio of co-surfactant to surfactant is from about 1/7 to about 1/2. In another embodiment of the amount of co-surfactant, will be from about 25 to about 75% v/v of the surfactant and from about 10 to about 55% v/v of the co-surfactant in the microemulsion.
The oily suspensions may be formulated as follows: the active ingredient is suspended in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bitterants, and flavoring agents can be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid or other known preservatives.
Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening and/or bittering agents, such as those described above.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are, for example, those already mentioned above. Additional excipients, for example sweetening, bittering, flavoring and coloring agents, may also be present.
Syrups or elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent, a preservative, a flavoring and/or a coloring agent.
In another embodiment of the invention, the composition can be in the form of a paste. Examples of paste form embodiments include, but are not limited to, those described in U.S. patent nos.6,787,342 and 7,001,889, each of which is incorporated herein by reference. In addition to the anthelmintic compound of the invention, the paste can also contain fumed silica; a viscosity modifier; a carrier; optionally, an absorbent; and optionally, a colorant, stabilizer, surfactant, or preservative.
The process for preparing the paste formulation comprises the following steps:
(a) dissolving or dispersing the anthelmintic compound into the carrier by mixing;
(b) adding fumed silica to the carrier containing the dissolved anthelmintic compound and mixing until the silica is dispersed in the carrier;
(c) allowing the intermediate formed in (b) to settle for a time sufficient to allow entrapped air to escape during step (b); and is
(d) The viscosity modifier was added to the intermediate with stirring to produce a homogeneous paste.
The above steps are exemplary and not intended to be limiting. For example, step (a) may be the final step.
In one embodiment of the formulation, the formulation is a paste containing at least one anthelmintic compound of formula (I), fumed silica, viscosity modifiers, absorbents, colorants; and a hydrophilic carrier which is glyceryl triacetate, monoglyceride, diglyceride, or triglyceride.
The paste may also include, but is not limited to, a viscosity modifier selected from PEG 200, PEG 300, PEG 400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or tween 80), and poloxamers (e.g., Pluronic L81); an absorbent selected from the group consisting of magnesium carbonate, calcium carbonate, starch, and cellulose and derivatives thereof; and a colorant selected from titanium trioxide, iron oxide, and FD & C Blue #1 ALUMINUMLAKE.
The compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art with those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that can be used, mention may be made in particular of water, ringer's solution and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol glycerol forms or polyethylene glycols may also be used. Preservatives such as phenol or benzyl alcohol may be used.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable compositions.
Topical, dermal and subcutaneous formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on, ready-to-use, pour-on and suspensions, dips and sprays. Topical administration of the compounds of the present invention or compositions comprising at least one compound of the present invention in an active agent, either as a spot-on or a pour-on composition, enables the compounds of the present invention to be absorbed through the skin to achieve a systemic effect, distributed throughout the sebaceous glands of the animal or distributed throughout the hair on the skin surface. Where the compounds are distributed across the sebaceous glands, they can act as reservoirs, whereby there can be a long lasting effect (up to several months). The spot-on formulations are generally applied to a localized area, which refers to an area other than the entire animal. In one embodiment of the localized region, the localized region is between the shoulders. In another embodiment of the localized region, it is a stripe, for example, a stripe from the head to the tail of the animal.
Pour-on formulations are described in U.S. patent No.6,010,710, incorporated herein by reference. Pour-on formulations may be oily and typically contain a diluent or vehicle and, if the active ingredient is not soluble in the diluent, a solvent for the active ingredient (e.g. an organic solvent).
Organic solvents useful in the present invention include, but are not limited to: acetyl tributyl citrate, fatty acid esters such as dimethyl ester, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol N-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl ethylamine, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidones (including N-methylpyrrolidone), diethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, ethylene glycol, diisobutyl adipate, diisopropyl adipate (also known as CEPRAPHYL 230), glyceryl triacetate, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethyl sulfoxide (dimethylsufoxide), organic amides (including dimethylformamide and dimethylacetamide), and diethyl phthalate, Or a mixture of at least two of these solvents.
In one embodiment of the invention, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises C1-C10Alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate, etc.), C10-C18Saturated fatty acids or esters thereof, C10-C18Monounsaturated fatty acids or esters thereof, mono-or diesters of aliphatic diacids, monoglycerides (e.g., monoglycerides), diglycerides (e.g., diglycerides), triglycerides (e.g., glycerol diesters)Triglycerides such as triacetin), glycols, glycol ethers, glycol esters or carbonates, various grades of polyethylene glycols (PEGs) or monoethers, diethers, monoesters or diesters thereof (e.g., diethylene glycol monoethyl ether), or mixtures thereof.
As vehicles or diluents, vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, coconut oil and the like; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, and the like; aliphatic or cyclic hydrocarbons or alternatively medium chain (such as C8 to C12) triglycerides, for example.
In another embodiment of the invention, softeners and/or spreaders and/or film formers may be added. In one embodiment, the softening and/or spreading and/or film forming agent is one selected from the group consisting of:
(a) polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, 2-pyrrolidone (including, but not limited to, N-methyl pyrrolidone), mannitol, glycerol, sorbitol, polyoxyethylated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils such as Polydimethylsiloxane (PDMS) oil, for example those containing silanol functional groups, or 45V2 oil,
(b) anionic surfactants such as alkali stearate, sodium stearate, potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietate; salts of alkyl sulfates (e.g., sodium lauryl sulfate and sodium cetyl sulfate); sodium dodecylbenzene sulfonate, dioctyl sodium sulfosuccinate; fatty acids (such as those derived from coconut oil),
(c) cationic surfactants, e.g. of formula N+R'R″R″′R″″，Y-Wherein the residue R is an optionally hydroxylated hydrocarbon residue and Y is-Anions that are strong acids such as halide, sulfate, and sulfonate anions; cetyl trimethylammonium bromide is among the cationic surfactants that can be used,
(d) formula N+An amine salt of HR ' R ', wherein residues R, R ', R ' and R ' are optionally independently hydroxylated hydrocarbon residues; octadecylamine hydrochloride is among the cationic surfactants that can be used,
(e) nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated (e.g., polysorbate 80), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols, such as polyoxypropylene-styrene ether; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids, copolymers of ethylene oxide and propylene oxide,
(f) amphoteric surfactants, such as substituted lauryl compounds of betaine; or
(g) Mixtures of at least two of these agents.
The concentration of solvent and anthelmintic compound of formula (I) and its solubility in the solvent will be used in proportion. Efforts should be made to achieve as small a volume as possible. Differences were made up to 100% with vehicle.
In one embodiment of the amount of the softening agent, the softening agent is used in a proportion of from 0.1 to 50% and 0.25 to 5% by volume.
In another embodiment of the present invention, the composition may be in the form of a ready-to-use solution, as described in U.S. patent No.6,395,765, incorporated herein by reference. In addition to the anthelmintic compounds of the present invention, the ready-to-use solution may contain a crystallization inhibitor, an organic solvent and an organic co-solvent.
In one embodiment of the amount of crystallization inhibitor, the crystallization inhibitor can be present in the composition in a proportion of from about 1 to about 30% (w/v). In other embodiments, the crystallization inhibitor may be present in a proportion of about 1% to about 20% (w/v), or about 5% to about 15%. Acceptable inhibitors are those that are added to the formulation at the time of administration of the formulation to inhibit crystal formation. In certain embodiments, the formulations may include compounds other than those listed herein that act as crystallization inhibitors. In these embodiments, the solubility of the crystallization inhibitor can be determined by experimentation in which 0.3ml of a solution containing 10% (w/v) of the anthelmintic compound of the present invention and 10% of the inhibitor in a liquid carrier is placed on a glass slide and allowed to stand for 24 hours at 20 ℃. The slides were then visually observed. Acceptable inhibitors are those added to the formulation to provide little (e.g., less than 10 crystals) or no crystallization.
In one embodiment, the organic solvent has a dielectric constant in the range of from about 2 to about 35, from about 10 to about 35, or from about 20 to about 30. In other embodiments, the solvent will have a dielectric constant between about 2 and about 20, or between about 2 and about 10. The content of the organic solvent in the total composition will make up to 100% of the composition.
As discussed above, the solvent may comprise a mixture of solvents, including a mixture of organic solvents and organic co-solvents. In one embodiment, the organic co-solvent has a boiling point of less than about 300 ℃ or less than about 250 ℃. In other embodiments, the co-solvent has a boiling point of less than about 200 ℃, or less than about 130 ℃. In yet another embodiment of the present invention, the organic co-solvent has a boiling point of less than about 100 ℃, or less than about 80 ℃. In still other embodiments, the organic co-solvent will have a dielectric constant in a range selected from about 2 to about 40, about 10 to about 40, or generally about 20 to about 30. In some embodiments of the invention, the co-solvent may be present in the composition in an organic co-solvent/organic solvent weight/weight (W/W) ratio of from about 1/15 to about 1/2. In some embodiments, to act as a drying promoter, the co-solvent is volatile and soluble in water and/or organic solvents.
The formulation may also contain an antioxidant intended to inhibit oxidation in air, the agent being present in a ratio selected from the range of about 0.005 to about 1% (w/v) and about 0.01% to about 0.05%.
Crystallization inhibitors useful in the present invention include, but are not limited to:
(a) polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, various grades of polyethylene glycol, benzyl alcohol, 2-pyrrolidone (including but not limited to N-methyl pyrrolidone), dimethylsulfoxide, mannitol, glycerol, polyoxyethylated esters of sorbitol or sorbitan; lecithin or sodium carboxymethyl cellulose; a solvent as described herein capable of inhibiting crystal formation; acrylic acid derivatives such as acrylates and polymethacrylates or other polymers derived from acrylic acid monomers, and the like;
(b) anionic surfactants such as alkaline stearates (e.g., sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates including, but not limited to, sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzene sulfonate or dioctyl sodium sulfosuccinate; or fatty acids (e.g., coconut oil);
(c) cationic surfactants, e.g. of formula N+R'R″R″'R″″Y-Wherein the R residues are the same or different optionally hydroxylated hydrocarbon residues and Y-Anions that are strong acids, such as halide, sulfate, and sulfonate anions; cetyl trimethylammonium bromide is one of the cationic surfactants that can be used;
(d) formula N+Amine salts of HR 'R', wherein the R residues are the same or different optionally hydroxylated hydrocarbon residues; octadecylamine hydrochloride is one of the cationic surfactants that can be used;
(e) nonionic surfactants, such as optionally polyoxyethylated esters of sorbitan, for example polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide;
(f) amphoteric surfactants, such as substituted lauryl compounds of betaine; or
(g) A mixture of at least two of the compounds listed in (a) to (f) above.
In one embodiment of a crystallization inhibitor, a crystallization inhibitor pair will be used. Such pairs include, for example, a combination of a polymeric type film former and a surfactant. These agents will be selected from the compounds mentioned above as crystallization inhibitors.
In one embodiment of the film forming agent, the agent is of the polymeric type including, but not limited to, grades of polyvinylpyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinylpyrrolidone.
In one embodiment of surfactants, agents include, but are not limited to, those composed of nonionic surfactants; in another embodiment of the surfactant, the agent is a polyoxyethylenated ester of sorbitan and in still another embodiment of the surfactant, the agent comprises various grades of polysorbate, such as polysorbate 80.
In another embodiment of the invention, the film former and surfactant can be added in similar or identical amounts within the limits of the total amount of crystallization inhibitor mentioned elsewhere.
The pairing thus formed ensures in a noteworthy manner the following objectives: the absence of crystallization on the outer skin and the maintenance of the cosmetic appearance of the skin or fur, i.e. the absence of a tendency to blocking or a tendency to sticky appearance even at high concentrations of active substance.
In one embodiment of the antioxidant, the agent is conventional in the art and includes, but is not limited to, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or a mixture of no more than two thereof.
The formulation aids discussed above are well known to practitioners in the art and may be obtained commercially or by known techniques. These concentrated compositions are generally prepared by simply mixing the components as defined hereinbefore; advantageously, the starting point is to mix the active substance in the main solvent and then add the other ingredients or adjuvants.
The volume of administration is not limited, so long as the amount of substance administered appears to be safe and effective. Generally, the volume of administration will depend on the size and weight of the animal, as well as the concentration of the active agent, the extent of the parasitic infestation, and the type of administration. In some embodiments, the administration volume may be from about 0.3 to about 5ml, or from about 0.3ml to about 1 ml. In one embodiment of the volume, the volume is on the order of about 0.5ml for cats and about 0.3 to about 3ml for dogs, depending on the animal weight.
In another embodiment of the invention, administration of the spot-on formulation according to the invention can also provide long-lasting and broad-spectrum efficacy in the case of administration of the solution to mammals or birds. Spot-on formulations provide for topical administration of concentrated solutions, suspensions, microemulsions or emulsions for application to a site on an animal at intervals, typically between the shoulders (spot-on type solutions).
For a spot-on formulation, the carrier may be a liquid carrier vehicle as disclosed in U.S. patent No.6,426,333 (incorporated herein by reference), and in one embodiment, the spot-on formulation comprises an agent and a co-solvent, wherein the agent is selected from the group consisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethyl sulfoxide, organic amides (including dimethylformamide and dimethylacetamide), ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxide, propylene glycol, 2-pyrrolidone (including N-methyl pyrrolidone), diethylene glycol monoethyl ether, ethylene glycol diether, diethyl phthalate fatty acid esters (such as diethyl ester or diisobutyl adipate), and mixtures of at least two of these agents, and the co-solvent is selected from anhydrous ethanol, isopropanol or methanol.
In one embodiment of the invention, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises C1-C10Alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate, etc.), C10-C18Saturated fatty acids or esters thereof, C10-C18Monounsaturated fatty acids or esters thereof, mono-or diesters of aliphatic diacids, monoglycerides (e.g., monoglycerides), diglycerides (e.g., diglycerides), triglycerides (e.g., glycerol diesters)Triglycerides such as triacetin), glycols, glycol ethers, glycol esters or carbonates, various grades of polyethylene glycols (PEGs) or monoethers, diethers, monoesters or diesters thereof (e.g., diethylene glycol monoethyl ether), or mixtures thereof.
The liquid carrier vehicle may optionally contain crystallization inhibitors including anionic surfactants, cationic surfactants, nonionic surfactants, amine salts, amphoteric surfactants or polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, 2-pyrrolidones including N-methylpyrrolidone (NMP), dimethylsulfoxide, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylated sorbitan esters; lecithin, sodium carboxymethylcellulose, solvents which inhibit the formation of crystals as defined herein, and acrylic acid derivatives such as acrylates or methacrylates and other polymers derived from acrylic acid monomers, or mixtures of these crystallization inhibitors.
Spot-on formulations may be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, spot-on formulations can be prepared by encapsulating the active ingredient so that residues of the therapeutic agent are left on the animal's surface. These formulations will vary with the weight of the therapeutic agent in the combination, which will depend on the type of host animal to be treated, the severity and type of infection and the host weight.
Each dosage form may contain from about 0.5mg to about 5g of active agent. In one embodiment of the dosage form, the dose is from about 1mg to about 500mg of active agent, typically about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 800mg, or about 1000 mg.
In one embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.05% to about 50% weight/volume. In other embodiments, the active agent may be present in the formulation at a concentration of about 0.1% to about 30%, about 0.5% to about 20% (w/v), or about 1% to about 10% (w/v). In another embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.1% to about 2% weight/volume. In yet another embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.25 to about 1.5% weight/volume. In yet another embodiment of the invention, the active agent is present in the formulation at a concentration of about 1% weight/volume.
In a particularly advantageous embodiment of the invention, the dose of the compound of the invention is from about 0.1mg/kg to about 100 mg/kg. In other embodiments, the dose of a compound of the invention is from about 0.5mg/kg to about 70mg/kg, from about 0.5mg/kg to about 50mg/kg, or from about 0.5mg/kg to about 30 mg/kg. In other preferred embodiments, the dose is from 0.5mg/kg to about 30mg/kg, from 0.5mg/kg to about 20mg/kg, or from 0.5mg/kg to about 10 mg/kg. More generally, in some embodiments, the dose of active compound is from about 0.1mg/kg to 5mg/kg, 0.1mg/kg to about 3mg/kg, or about 0.1mg/kg to about 1.5 mg/kg. In still other embodiments of the invention, the dosage may be as low as 0.1mg/kg (0.02mg/ml), about 0.2mg/kg (0.04mg/ml), about 0.3mg/kg (0.06 mg/ml), about 0.4mg/kg (0.08mg/ml), about 0.5mg/kg (0.1mg/ml), about 0.6mg/kg (0.12mg/ml), about 0.7mg/kg (0.14mg/ml), about 0.8mg/kg (0.16mg/ml), about 0.9mg/kg (0.18mg/ml), about 1.0mg/kg (0.2 mg/ml).
Another embodiment of the invention is directed to a method of treating an endoparasitic infestation or infection in an animal comprising administering to an animal in need thereof an effective amount of a compound of the invention. The compounds of the invention have been shown to have excellent efficacy against endoparasites, in particular against parasites that are resistant to macrolide actives. For example, the compounds of the present invention have shown superior efficacy against ivermectin-resistant endoparasites in sheep. Oral administration of a compound of the invention (compound 3.024) at a dose of 1.5mg/kg or 3mg/kg had greater than 95% efficacy against ivermectin-resistant strains of Haemonchus contortus (Haemonchus contortus), Ostertagia circulans (Ostertagia circurntica) and Trichostrongylus columnifera. In contrast, ivermectin is almost completely inactive against Haemonchus contortus at a dose of 0.2mg/kg, less than 30% effective against Oersteus circulans and less than 60% effective against Trichostrongyus columbriformis. It is surprising that the compounds of the invention have excellent efficacy against endoparasites that are resistant to ivermectin, one of the most effective agents known to be active against endoparasites and ectoparasites.
Thus, in another embodiment, the invention provides a method for treating an endoparasitic infestation or infection in an animal comprising administering to an animal in need thereof an effective amount of an anthelmintic compound of the invention in combination with an effective amount of an invertebrate GABA receptor activator (including abamectin or milbemycin). Avermectins that may be used in combination with the compounds of the present invention include, but are not limited to, abamectin, dimadectin, doramectin, emamectin (emamectin), eprinomectin, ivermectin, latidectin (latidectin), lepimectin and selamectin. Milbemycin compounds that may be used in combination with the compounds of the present invention include, but are not limited to, milbemectin (milbemectin), milbemycin D, moxidectin, and nemadectin (nemadectin). Also included are 5-oxo and 5-oxime derivatives of said avermectins and milbemycins.
In one embodiment, the compounds and compositions of the present invention may be used to treat infections or infestations by endogenous parasites (endoparasidiic), including, but not limited to, tapeworm (Anoplocephala), ancylostomia (Ancylostoma), Anecator, Ascaris (Ascaris), bruxiella (Brugia), peronopostoma (bunolosum), capillaris (Capillaria), cabebretta (Chabertia), Cooperia (Cooperia), cyathosum, cylicomycotos, cycloodontophorus, cyclosporus, dictyotus (dichycaulus), dipterus (dipterylostomia), dipterylostomia (dipteroides), diplopodium (trichoderma), trichoderma (dipteroides), trichoderma (trichinella), trichoderma (trichia), trichoderma (echinacea), trichoderma (echinacea), trichoderma (neospora), trichoderma (neospora, Oesphagosteumum, Onchocerca (Onchocerca), Ostertagia (Ostertagia), Ostertagia (Oxyuris), Paraascaris (Paraascaris), Schistosoma (Schistosoma), Strongyloides (Strongylous), Taenia, Toxocarb (Toxocara), Strongyloides (Strongyloides), Toxoasca (Toxascaris), Trichinella (Trichinella), Trichuris (Trichuris), Trichostrongylus (Trichostrongylus), Uncinia (Uncinaria), Bruguia (Wuchereria), and combinations thereof.
In a particularly preferred embodiment of the invention, the compounds and compositions of the invention are used to treat or prevent heartworm infection. In another embodiment, the compounds and compositions of the invention are used for the treatment or prevention of Dirofilaria repens (Dirofilaria repens) infection.
In another embodiment of the invention, the helminths are Haemonchus contortus (Haemonchus contortus), Ostertagia circutita, Trichostrongylus axaei (Trichostrongylus axei), Trichostrongylus hyalinus (Trichostrongylus colubrica), Coopilus brevifolia (Cooperia curtici), Trichostrongylus tenuii (Nematodirus battus) and combinations thereof.
Another embodiment of the invention is directed to a method of treating an ectoparasite infestation or infection in an animal in need thereof, which comprises administering to the animal in need thereof an effective amount of a compound of the invention.
In one embodiment, the infection or infestation is caused by fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof.
In yet another embodiment, the present invention provides a method of treating an ectoparasite infestation or infection in an animal comprising administering to an animal in need thereof an effective amount of an anthelmintic compound of the present invention in combination with an effective amount of an avermectin or milbemycin active.
In some embodiments, the compounds of the present invention are useful for protecting plants and crops. In other embodiments, the compounds may be used to treat environmental surfaces and structures.
The compounds of formula (I) or their salts can be used as such or in the form of their preparations (formulations) as a combination with other active substances, such as, for example, insecticides, attractants, fungicides, acaricides, nematicides and with plant growth regulators.
Fungicides include, but are not limited to, bronopol, dichlorophen, triclopyr, nickel dimethyldithiocarbamate, kasugamycin, octulone, furoic acid (furancarboxylic acid), oxytetracycline, probenazole, streptomycin, phylloxtalide (tecloftalam), copper sulfate, and other copper formulations.
Insecticides/acaricides/nematicides include those compounds mentioned in U.S. patent nos.7,420,062 and 7,001,903, U.S. patent publication 2008/0234331 (each incorporated herein by reference), and compounds classified by irac (insecticide Resistance Action committee). Examples of insecticides/acaricides/nematicides include, but are not limited to: a carbamate; triazamate (triazemate); an organic phosphate; a cyclic diene organochlorine; a phenyl pyrazole; DDT; methoxy chloride; pyrethrins (pyrethiides); removing insect and chrysanthemum essence; neonicotinoids (neonicotinoids); nicotine; monosultap (bensultap); badan hydrochloride; a nereismycin analog; spinosyns (spinosyns); abamectin and milbemycin; juvenile hormone analogs; fenoxycarb; fenoxycarb; an alkyl halide; nitrotrichloromethane; sulfur fluoride; cryolite; pymetrozine; flonicamid (flonicamid); clofentezine; hexythiazox; etoxazole (etoxazole); a coccobacillus; diafenthiuron (diafenthiuron); an organotin acaricide; propargite; tetrachloro diphenyl sulfone; chlorfenapyr; DNOC; a benzoylurea; buprofezin; cyromazine; dihydrazides (diacylhydrazines); azadirachtin; amitraz; hydramethylnon; miticidal quinones; fluacrypyrim (fluacrypyrim); a METI acaricide; rotenone; indoxacarb (indoxacarb); metaflumizone (metaflumizone); 4-glycoloacetolide derivatives; aluminum phosphide; a cyanide compound; a phosphine; bifenazate (bifenazate); fluoroacetate; a P450-dependent monooxygenase inhibitor; an esterase inhibitor; a diamide; fenpyroximate; killing mites and releasing mites; kaile san; pyridalyl (pyridalyl); borax; antimony potassium tartrate; fumigants, such as methyl bromide; a ditera; clandosan; sincocin.
The compounds of formula (I) may be formulated in different ways depending on the prevailing biological and/or chemo-physical parameters. Examples of possible suitable formulations are: wettable Powders (WP), water-Soluble Powders (SP), water-soluble concentrates, Emulsifiable Concentrates (EC), Emulsions (EW) such as oil-in-water and water-in-oil emulsions, sprayable emulsions, Suspension Concentrates (SC), oil-or water-based dispersions, oil-soluble solutions, Capsule Suspensions (CS), Dusts (DP), seed dressing products, granules for sowing and soil applications, granules in particulate form (GR), spray granules, coated granules and adsorbent granules, water-dispersible granules (WG), water-Soluble Granules (SG), ULV formulations, microcapsules and waxes.
Solid State forms of the compounds of formula (I) can be prepared by methods known in the art, for example, Byrn et al, "Solid-State Chemistry of Drugs", 2 nd edition, SSCI Inc. (1999); glucker et al, "CrystalStructure Analysis-A PrimeR", 2 nd edition, Oxford University Press, (1985).
The formulations mentioned may be prepared in a manner known per se, for example by mixing the active compounds with at least one solvent or diluent, emulsifier, dispersant and/or binder or fixative, water repellent and optionally one or more drying agents, UV stabilizers, colorants, pigments and other processing aids.
These individual formulation types are known in principle and are described, for example, in Winnacker-K ü chler, "Chemische Technology" [ Chemical Technology ], Volume 7, C.Hauser Verlag, Munich, 4 th edition 1986, "Wade van Valkenburg," Pesticide Formulations ", Marcel Dekker, N.Y., 1973; K.Martens," Spray Drying Handbook ", 3rd Ed.1979, G.Goodwin Ltd.London.
The necessary formulation auxiliaries such as inert materials, surfactants, solvents and other additives are also known and described, for example: watkins, "Handbook of Instrument Dust Diluents and Cariers", 2 nd edition, Darland Books, Caldwell N.J.; olphen, "Introduction to Clay colloid chemistry", 2 nd edition, J.Wiley&Sons,N.Y.；C.Marsden,″Solvents Guide", 2 nd edition, Interscience, N.Y.1963; McCutcheon's "Detergents and Emulsifiers Annual", MCPubl.Corp., Ridgewood N.J.; sisley and Wood, "Encyclopedia of Surface active Agents", chem.publ.Co. Inc., N.Y.1964;
Figure BDA0001193146030001181
[Surface-activeethylene oxide adducts],Wiss.Verlagsgesell., Stuttgart 1976；Winnacker-Küchler,″Chemische Technologie″ [Chemical Technology],Volume 7,C.Hauser Verlag,Munich,4th Ed.1986。
wettable powders are formulations which are uniformly dispersed in water and which, in addition to the compounds of the formula (I), also comprise ionic and/or nonionic surfactants (wetting agents, dispersants), for example polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols, polyoxyethylated fatty amines, sulfates of fatty alcohol polyglycol ethers, alkylsulfonates or alkylbenzenesulfonates, sodium lignosulfonates, sodium 2,2 '-dinaphthylmethane-6, 6' -disulfonate, sodium dibutylnaphthalenesulfonate or other sodium oleoylmethyltaurates, in addition to diluents or inert materials. For the preparation of wettable powders, the compounds of the formula (I) are, for example, finely ground in customary apparatus, such as hammer mills, pressure-charged mills and air-jet mills and simultaneously or subsequently mixed with formulation auxiliaries.
Emulsifiable concentrates are prepared, for example, by dissolving a compound of formula (I) in an organic solvent (e.g., butanol, cyclohexanone, dimethylformamide, xylene or other high boiling aromatic or hydrocarbon or mixtures of these) and adding one or more ionic and/or nonionic surfactants (emulsifiers). Useful emulsifiers are, for example: calcium salts of alkylaryl sulfonic acids, such as calcium dodecylbenzenesulfonate or nonionic emulsifiers, such as fatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcohol polyglycol ethers, propylene oxide/ethylene oxide concentrates, alkyl polyethers, sorbitan esters, such as sorbitan fatty acid esters, or polyoxyethylene sorbitan esters, such as polyoxyethylene sorbitan fatty acid esters.
Dusts are obtained by grinding the active substance with finely divided solid substances, for example talc or natural clays, such as kaolin, bentonite or pyrophyllite, or diatomaceous earth.
Suspension concentrates may be water-based or oil-based. They can be prepared, for example, by wet grinding with the aid of commercially available sand mills, if appropriate with addition of surfactants as already mentioned above in the case of the other formulation types.
Emulsions, for example oil-in-water Emulsions (EW), can be prepared, for example, with the aid of stirrers, colloid mills and/or static mixtures using aqueous organic solvents and, if appropriate, surfactants as already mentioned above in the case of the other formulation types.
Granules can be prepared by spraying the compounds of the formula (I) onto the adsorption mass, granulated inert mass or by concentrating the active substance onto carrier surfaces such as sand, kaolinite or granulated inert mass with the aid of binders, for example polyvinyl alcohol, sodium polyacrylate or alternatively mineral oils. If desired in admixture with fertilizers, suitable active substances can also be granulated in the customary manner of fertilizer granule products.
Water dispersible granules, generally, are prepared by conventional methods such as spray drying, fluid bed granulation, pan granulation, mixing in a high speed mixer and extrusion in the absence of solid inert materials. For the preparation of pan, fluidized bed, extruder and Spray granules see, for example, in "Spray-Drying Handbook" 3rd ed.1979, g.goodwin ltd., London; e.browning, "Agglomeration", Chemical and Engineering 1967, pages 147 etseq; "Perry's Chemical Engineer's Handbook", 5th Ed., McGraw-Hill, New York1973, p.8-57. Typically, the agrochemical formulation comprises a range of about 0.1 to about 99% by weight and about 0.1 to about 95% by weight of a compound selected from formula (I).
The concentration of the compounds of the formula (I) in the wettable powders is, for example, about 10 to 90% by weight, the remainder being up to 100% by weight of the constituents of customary formulations. In the case of emulsifiable concentrates, the concentration of the compound of formula (I) may approach a range selected from about 1% to 90% and about 5% to about 80% by weight. Formulations in powder form typically comprise a compound of formula (I) selected from the range of about 1% to about 30% by weight of a compound of formula (I) in the range of about 5% to about 20% by weight. The spray solution comprises a compound of formula (I) selected from the group consisting of in the range of about 0.05% to about 80% by weight and in the range of about 2% to about 50% by weight. In the case of water dispersible granules, the content of the compound of formula (I) depends in part on whether the compound of formula (I) is in liquid or solid form and on the granulation aid, filler, etc. used. The water dispersible particles, for example, comprise a range between about 1% to about 95% and about 10% to about 80% by weight.
In addition, the formulations of the compounds of the formula (I) mentioned comprise, if appropriate, in each case customary binders, wetting agents, dispersants, emulsifiers, penetrants, preservatives, antifreeze agents, solvents, fillers, carriers, colorants, antifoams, evaporation inhibitors, pH regulators and viscosity regulators.
Additional pharmaceutically or veterinarily acceptable active ingredients may also be added to the compositions of the present invention. In certain embodiments, the additional active agent may be one or more parasiticidal compounds, including acaricides, anthelmintics, endectocides, and insecticides. Antiparasitic active agents may include ectoparasitic and endoparasitic agents.
Additional pharmaceutical agents that may be included in The compositions of The invention containing anthelmintic compounds of The invention are well known in The art (see, e.g., Plumb' vestary Drug Handbook, 5th edition, ed. donald c. Plumb, Blackwell Publishing, (2005) or The Merck vestary Manual, 9 th edition, (January2005)) and include, but are not limited to, acarbose, acepromazine maleate, acetaminophen, acetazolamide sodium, acetic acid, acetohydroxyamine, acetylcysteine, abamectin a, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, allyl pregnen, amantadine, amikacin sulfate, aminocaproic acid, amine valeramide bisulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphotericin B deoxycholate.Lipid-based amphotericin B (amphotericin B lipid-based), ampicillin, apremine, antacids (oral), antivenin, apomorphine, apremorphine sulfate, ascorbic acid, asparaginase, aspirin (aspiring), atenolol, altemezole, atracurium besylate, atropine sulfate, auranofin (aurnofin), chlorthioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, clobecholine, bisacodyl, bismuth subsalicylate, bleomycin sulfate, undecapreone, bromide, bromocriptine mesylate, budesonide, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, calcitonin, calcitriol, calcium salts, captopril (sodium bicarbonate), benorine, benomyl (indoxyl), benazelate (indoxyl), benazepril, benorine, benazepril (benorine), benorine, benori, Carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, ceftizolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur, ceftriaxone sodium (ceftiaxone sodium), cephalexin, cephalosporin, cefapirin, carbon (active), chlorambucil, chloramphenicol, chlorambucil, chlorpheniramine, chlorp
Figure BDA0001193146030001211
Chlorine and nitrogen
Figure BDA0001193146030001212
+/-Clilium Bromide, chlorothiazide, chlorpyrifos maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, clonazepam, clonidine, sodium chloroprostenol, dipotassium clonazepam, chlorpropamide, chlordiazepoxide, chlordiaz
Figure BDA0001193146030001213
Clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH)Icosapetastatin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene, chlorcosyl, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate (deslorelin acetate), desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane (dexrazoxane), dextran, diazepam, diazoxide (oral), diclofenamide, diclofenac sodium, dicloxacillin, diethylethazine citrate, Diethylstilbestrol (DES), difloxacin, digoxin, Dihydrotachysterol (DHT), Diltiazem (DHT)
Figure BDA0001193146030001214
Theohydramine, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenhydramine, propiram phosphate, dobutamine, docusate sodium/DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, polycyclocetin, calcium sodium edetate, calcium EDTA, etholammonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, recombinant human erythropoietin (epoetin)/erythropoietin, eprinomectin, etamol, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/sodium etanidate, ethanol (alcohol), etidronate, etodolac, etomidate, eutran, w/pentobarbital, famotidine, fatty acids (essential/omega), Felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride (finasteride), fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxamine maleate (fluvoxamineate), methylpyrazole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agent, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerol (oral), glycopyrrolate, gonadorelin (gonadorelin)Griseofulvin, guaifenesin, halothane, and glutamic hemoglobin (hemoglobin) -200
Figure BDA0001193146030001221
Heparin, hydroxyethyl starch, sodium hyaluronate, hydralazine (hydrazaline), hydrochlorothiazide, dihydrocodeinone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, dimalexanide dipropionate (imidocarbdiprinate), thiomycin-cilastatin sodium (imipenem-cilastatin sodium), imipramine, amrinone lactate (inamidone lactate), insulin, interferon α -2a (human recombinant), iodide (sodium/potassium), ipexol (syrup), sodium ioprotide, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsulalin, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, leuprolerin, levamisole, levovirethracetam, levovirin, levonorgestrel, meclolidine, lidocaine, clindamine, hydramine, trimethoprim, meclozine, meclofenoxapride, meclofenoxaprine, meclozine, meclofenoxapride, meclofenoxaprine, meclozine, meclofenoxapril, meclozine, meclofenoxate, meclofenoxapril, mecloxapril, meclofenoxapril, mecloxapril, meclofenoxapril, mecloxapril, meclofenoxapril, mecloxapril, meclofenoxapril, meclizine, meclofenoxapril, mecOctreotide acetate, olsalazine sodium (olsalazine sodium), omeprazole (omeprazole), ondansetron, opiate antidiarrheals (opitate antidiarrails), orbifloxacin, oxacillin sodium, oxazepam, oxybutynin (oxibutynin chloride), oxymorphone, oxytetracycline (oxytetracycline), oxytocin, disodium pamidronate, pancreatiprpase (pancreateprepase), pancuronium bromide, paromomycin sulfate, paroxetine (parozetine), penicillamine, semaphorin, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone (phymbuzone), norepinephrine, phenylpropanolamine, phenytoin sodium, pheromone, non-oral phosphate, phytoalexin K, pyridoxine K, piroxicam 1, piroxicam chloride, piroxicam, and piroxicam, Ponazuril, potassium chloride, prasuzuril, prazosin, benazelon/prednisone, promethamine, procarbazine, prochlorperazine, propantheline bromide, propionibazine, propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrophilic mucilage, pirstine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosylmethionine (SAMe), salts/hyperosmolar purgatides, selamectin, selegiline/1-desorpiline, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate (sodum thiosulfonate), growth hormone, taraxolol, spectinolide, sultone, stanozolol, streptokinase, isoprothiolane, propranolol, protanolone, protamine, prop, Streptozotocin, dimercaptosuccinic acid, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachloropyridazine sodium, sulfadiazine/trimethoprim (trimethroprim), sulfamethoxazole/trimethoprim, sulfadimethoxine (sulfadiminoxine), sulfadimethoxine/ormoprim (ormetoprim), sulfasalazine, taurine, tepoxaline (tepoxaline), terbinafine (terbinafine), terbutaline sulfate, testosterone, tetracycline, thiamine sodium, thiamine, thioguanine, thiopentontrine, thiotepa, thyrotropin, thiamine, thiotepa, sultepa, sufentanilTicarcillin disodium (ticarcillin disodium), teletamine/zolazepam, tilmicosin (tilmcosin), tiopronin (tiopronin), tobramycin sulfate, tocainide, tolazanine, tolfenamic acid (telfenamic acid), topiramate, tramadol, triamcinolone acetonide (trimcinolone acetonide), trientine, trostan, isoxazine tartrate w (trimeprazine tartrate)/prednisolone, tripelennamine, tylosin, ursodeoxycholic acid (urosio), valproic acid, vanadium, vancomycin, vasopressin, vecuronium, verapamil sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yobin, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zoniprazole, and mixtures thereof.
In one embodiment of the present invention, arylpyrazole compounds, such as phenylpyrazoles, are known in the art to be useful in combination with anthelmintic compounds of the present invention. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. patent nos.6,001,384; 6,010,710, respectively; 6,083,519, respectively; 6,096,329, respectively; 6,174,540, respectively; 6,685,954 and 6,998,131 (herein incorporated by reference in their entirety, each assigned to Merial, ltd., Duluth, GA). One particularly preferred arylpyrazole compound is fipronil (fipronil).
In another embodiment of the invention, one or more macrocyclic lactones, or lactams, which act as acaricides, anthelmintics, and/or insecticides, may be added to the compositions of the invention.
Macrolides include, but are not limited to, avermectin analogs such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin (lepimectin), selamectin and ML-1,694,554, and milbemycin analogs such as milbemectin (milbemectin), milbemycin D, milbemycin oxime, moxidectin and nemadectin. 5-oxo and 5-oxime derivatives of said avermectins and milbemycins are also included. Examples of combinations of arylpyrazole compounds with macrolides include, but are not limited to, those described in U.S. patent nos.6,426,333; 6,482,425, respectively; 6,962,713, respectively; and 6,998,131 (incorporated herein by reference in their entirety, each assigned to Merial, ltd., Duluth, GA).
Macrolide compounds are known in the art and can be readily obtained commercially or by synthetic techniques known in the art. Reference is made to widely used technical and commercial literature. For avermectins, Ivermectin and Abamectin, reference may be made, for example, to the works "ivermectins and abamectins", 1989, authors m.h. fischer and h.mrozik, William c.campbell, by Springer verlag, or
Figure BDA0001193146030001251
Et al (1981), "Avermectins Structure Determination", J.Am.chem.Soc.,103, 4216-. For doramectin, reference may be made to "Veterinary Parasitology", vol.49, No.1, July 1993, 5-15. For the milbemycins, reference may be made, inter alia, to Davies H.G. et al, 1986, "Avermectins and Milbemycins", nat. Prod.Rep.,3, 87-121, Mrozik H. et al, 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett.,24, 5333. beta. 5336, U.S. Pat. No.4,134,973 and EP 0677054, both of which are incorporated herein by reference.
Macrolides are natural products or semi-synthetic derivatives thereof. The structures of avermectins and milbemycins are closely related, for example, by sharing a complex 16-membered macrolide ring. Natural products abamectin are disclosed in U.S. patent No.4,310,519 and 22, 23-dihydroabamectin compounds are disclosed in U.S. patent No.4,199,569. U.S. patent nos.4,468,390, 5,824,653, EP 0007812 a1, U.K. patent specification 1390336, EP 0002916, and especially new zealand patent No. 237086 are also mentioned (incorporated herein by reference in their entirety). Naturally occurring milbemycins are described in U.S. patent No. 3,950,360 (incorporated herein by reference) and The Merck Index "12thed.,S.Budavari,Ed.,Merck&A number of references in use in co, inc. Latidectin is described in "International Nonproprietary Names for pharmaceutical Substances (INN)", WHO Drug Information, vol.17, No.4, pp.263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, inIn U.S. patent nos.5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148 and EP 0667054 (incorporated herein by reference in their entirety).
In another embodiment of the invention, the compositions may include a class of acaricides or insecticides known as Insect Growth Regulators (IGRs). Compounds belonging to this class are well known to practitioners and represent a wide variety of compound classes. These compounds all act by interfering with the development or growth of pests. Insect growth regulators are described, for example, in U.S. patent nos.3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179022 or U.K. 2140010 and U.S. patent nos.6,096,329 and 6,685,954 (incorporated herein by reference in their entirety).
In one embodiment, the IGR that may be included in the composition is a mimetic juvenile hormone compound. Examples of juvenile hormone mimics include azadirachtin (azadirachtin), bendiolol (diofenolan), fenoxycarb, methoprene, pyriproxyfen, tetrandrin, and 4-chloro-2 (2-chloro-2-methyl-propyl) -5- (6-iodo-3-pyridylmethoxy) pyridazin-3 (2H) -one. In a particularly preferred embodiment, the composition of the invention comprises methoprene or pyriproxyfen.
In another embodiment, the compositions of the present invention may comprise an IGR compound, which is an inhibitor of chitin synthesis. Chitin synthesis inhibitors include clofluazuron, ciprofloxacin, diflubenzuron, flurtamone, epoxiconazole, flufenoxuron, hexaflumuron, chlorfenoxuron, tebufenozide, teflubenzuron, triflumuron, novaluron, 1- (2, 6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenylurea, 1- (2, 6-difluoro-benzoyl) -3- (2-fluoro-4- (1,1,2, 2-tetrafluoroethoxy) -phenylurea, and 1- (2, 6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea.
In yet another embodiment of the present invention, adulticide insecticides and acaricides may also be added to the composition of the present invention. These include pyrethrins (which include guaethrin I, guaethrin II, jasmonate I, jasmonate II, pyrethrin I, pyrethrin II, and mixtures thereof) and pyrethrins, as well as carbamates, which include, but are not limited to, benomyl, cloxacarb, carbaryl, carbofuran, methomyl (methomyl), metolcarb, lufenuron, phenyl methyl o-isopropoxycarbamate, methomyl, carbosulfan, oxamyl, carbofuran, and monocarb.
In some embodiments, the compositions of the present invention may be combined with one or more anti-nematode agents, including, but not limited to, active agents in benzimidazole, imidazothiazole, tetrahydropyrimidine, and organophosphorous compounds. In some embodiments, benzimidazoles, including but not limited to thiabendazole, canabendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiofanate (thiophanate) and its o, o-dimethyl analogs may also be included in the composition.
In other embodiments, the compositions may include imidazothiazole compounds, including but not limited to tetramisole, levamisole, and butamifazole. In still other embodiments, the compounds of the present invention may include tetrahydropyrimidine active agents, including but not limited to pyrantel, oxclartel, and morantel. Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorophosphate, haloxon, naphthalenephosphine and dichlorvos, heptenophos, methamphetamine, monocrotophos, TEPP, and setrophos.
In other embodiments, the compositions may include as neutral compounds the anti-nematode compounds phenothiazine and piperazine, or in various salt forms, diethylcarbamazine, phenols such as diiodonitrophenol, arsenicals such as arsenamide, ethanolamines such as benzophentermine, tioxyammonium closylate and methoxidine, cyanine dyes including pyritinomine, enbovinium and dithiine, isothiocyanates including dithiocyanbenzene, suramin sodium, phthalhexidine esters and various natural products including, but not limited to, hygromycin B, α -santonine and kainic acid.
In other embodiments, the compositions of the invention may include an anti-nematode agent. Suitable anti-nematode agents include, but are not limited to, oleandomycin such as oleandomycin D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives, oltipraz, tiarone, haynone, oxanil, nitrothiocyanamide, nilidazole, nitrolobenzonitrile, various bisphenol compounds known in the art (including hexachlorophene, thiochlorophene, thiobischlorophene sulfoxide and bischloronitrophenol); various salicylanilide compounds including tribromosalan, hydroxychlorozamide, cloiodoxanide, rafoxanide, britinide, brixanide and closantel, triclabendazole, difenidol, clorsulone, trichloropiperazines and emidine.
Anti-nematode compounds may also be conveniently used in the compositions of the present invention, including, but not limited to, various forms of arecoline, bunamidine, niclosamide, nitrothiocyantate, paromomycin, and paromomycin I I.
In still other embodiments, the compositions of the present invention can include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, chlorfenapyr, chlordane, DDT, endosulfan, lindane, methoxychloride, toxaphene, bromophos-ethyl, carbophos, chlorfenphos, chlorpyrifos, bacon, methidathion, dipirothion, diemthoate, dioxathion, ethion, sulfamethoxazole, fenitrothion, fenthion, fosaprate, iodophos, malathion, tribromophos, vophos, phosmet, oxime phos, amirocarb, tetaphos, sethoxydim, allethrin, cyhalothrin, deltamethrin, fenvalerate, flucythrin, methicillin, phenothrin, pyrethrin, resmethrin, benfurethrin, benzyl ester, carbon disulfide, crotamiton, difluorobenzone, diphenylamine, disulfiram, thiocyanoacetate, fenazalen, fenacetrin, sulbactam, dinotefuran, butyrin, butyrophenone, stannate, fenproxyfen, tin hydroxide, fenprox, tin hydroxide, fenprox, thiocatde, thiocyanotoxin, thiocyan, Deet, deet ester and the compounds 1,5a,6,9,9a,9 b-hexahydro-4 a (4H) -dibenzofuran formaldehyde (MGK-11), 2- (2-ethylhexyl) -3a,4,7,7 a-tetrahydro-4, 7-methylene-1H-isoindole-1, 3(2H) dione (MGK-264), dipropyl-2, 5-pyridinedicarboxylate (MGK-326) and 2- (octylthio) ethanol (MGK-874). In a particularly preferred embodiment, the compositions of the invention will comprise a combination of permethrin and the anthelmintic compounds of the invention.
An antiparasitic agent that may be combined with the compounds of the present invention to form a composition may be a biologically active peptide or protein, including but not limited to cyclic depsipeptides, that act at neuromuscular junctions by stimulating presynaptic receptors belonging to the secretin receptor, resulting in paralysis or death of the parasite. In one embodiment of the depsipeptide, the depsipeptide is Emolsium @ (see Willson et al, Parasitology, Jan.2003,126(Pt 1): 79-86). In another embodiment, the cyclic depsipeptide is PF1022A (see, e.g., US 5,116,815, which is incorporated herein by reference) or a derivative thereof.
In another embodiment of The invention, The composition may include a spinosyn active produced by Saccharopolyspora spinosa (Saccharomyces spinosa) of The genus Actinomyces (see, e.g., Salgado V.L. and SparksT.C., "The Spinosyns: Chemistry, Biochemistry, model of Action, and Resistance," in comprehensive Molecular Instrument Science, vol.6, pp.137-173, 2005) or a semi-synthetic spinosyn (spinoid) active. Spinosyns are commonly referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, 0, P, Q, R, S, T, U, V, W, or Y, and any of these components or combinations thereof can be used in the compositions of the present invention. The spinosyn compound may be a 5,6, 5-tricyclic ring system fused to a 12-membered macrolide, a neutral sugar (rhamnose), and an amino sugar (forsamine). These and other natural spinosyn compounds (including 21-butene spinosyn produced by saccharomyces parcospora pagona) that may be used in the compositions of the present invention may be produced by fermentation by conventional methods known in the art. Other spinosyn compounds that may be used in the compositions of the present invention are disclosed in U.S. patent nos.5,496,931; 5,670,364, respectively; 5,591,606, respectively; 5,571,901, respectively; 5,202,242; 5,767,253, respectively; 5,840,861, respectively; 5,670,486, respectively; 5,631,155 and 6,001,981, all of which are incorporated herein by reference in their entirety. The spinosyn compound may include, but is not limited to, spinosyn a, spinosyn D, spinosad, spinetoram (spinetoram), or a combination thereof. Spinosad is a combination of Spinosad A and Spinosad D, and spinetoram is a combination of 3 '-ethoxy-5, 6-dihydrospinosad and 3' -ethoxyspinosad L.
In another embodiment, the compositions of the present invention may include an active agent from the class of neonicotinoid insecticides. Neonicotinoids bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that may be included in the composition of the invention is imidacloprid. Imidacloprid is a well-known neonicotinoid active agent and is a topical parasiticidal product marketed by Bayer Animal Health (Bayer Animal Health)
Figure BDA0001193146030001291
II, K9
Figure BDA0001193146030001292
And K9
Figure BDA0001193146030001293
II key active ingredients. Such agents are described, for example, in U.S. patent No.4,742,060 or EP 0892060.
In another embodiment, the composition of the invention may include nyxatin, another active agent of neonicotinoid insecticides. Nicotine blue is an oral product CAPSTAR sold by Novartis Animal HealthTMActive ingredient in the tablet.
In some embodiments, the pesticide that may be combined with the compositions of the present invention is a semicarbazone, such as metaflumizone.
In another embodiment of the invention nodulisporic acid and its derivatives (a known acaricide, anthelmintic, antiparasitic and insecticide) may be added to the composition of the invention. These compounds are useful for treating or preventing infections in humans and animals, for example, in U.S. patent nos.5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference in their entirety. The compositions may include one or more nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above-referenced patents.
In another embodiment, anthelmintic compounds such as monentule (ZOLVIX), and the like, of the aminoacetonitrile type (AAD) compounds may be added to the compositions of the present invention. Such compounds are described, for example, in WO 2004/024704 and u.s patent No.7,084,280 (incorporated herein by reference); sager et al, vetertiary Parasitology,2009, 159, 49-54; kaminsky et al, Nature vol.452,13 March 2008, 176-. The compositions of the present invention may also be combined with arylpyrrole (aryloazol) -2-yl cyanoethylamino compounds such as those described in US patent No.8,088,801 to Soll et al, which is incorporated herein in its entirety, and thioamide derivatives of these compounds, as described in u.s patent No.7,964,621, which is also incorporated herein by reference.
The compositions of the invention may also be combined with paraherquamide compounds and derivatives of these compounds, including dequaline (see Ostlind et al, Research in Veterinary Science,1990,48, 260-61; and Ostlind et al, Medical and Veterinary biology, 1997,11, 407-. The Paraherquamide family of compounds is a known compound which includes the spiroheptine (spirodioxepino) indole nucleus which has activity against certain parasites (see Tet. Lett.1981,22, 135; J. antibiotics1990,43,1380, and J. antibiotics 1991, 44, 492). Additionally, compounds structurally related to the family of marcfortines, such as marcfortines a-C, are also known and can be combined with the formulations of the present invention (see j. chem. soc. -chem. comm. 1980,601 and tet. lett.1981,22,1977). Further references to paraherquamide derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432, U.S. patent 5,703,078 and U.S. patent 5,750,695, all incorporated herein by reference in their entirety.
In another particularly preferred embodiment, the compositions of the present invention may conveniently comprise one or more compounds of the isoxazoline class. Such active agents are described in WO 2007/079162, WO 2007/075459 and US2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, US 7,662,972, WO 2008/122375, WO 2010/003877, WO 2010/003923, WO2009/025983, WO 2008/150393, WO 2008/154528, WO 2009/045999, WO 2009/051956, WO2009/126668, WO 2009/0259832, WO 2008/109760, US 2009/0156643, US 2010/0144797, US 2010/0137612, US 2011/009438 and WO 2011/075591, all incorporated herein by reference in their entirety.
Anthelmintics, parasiticides and insecticides may also be selected from the above compounds suitable for agrochemical use, where appropriate.
Typically, the additional active agent is included in a dose of between about 0.1 μ g to about 500 mg. In certain embodiments, the additional active agent may be present in a dose of about 1mg to about 500mg, about 1mg to about 300mg, about 1mg to about 100 mg. In other embodiments, the additional active agent may be present in an amount of about 1mg to about 50mg or about 1mg to about 20 mg. In other embodiments of the invention, the additional active agent is included in a dose of about 1 μ g to about 10 mg.
In another embodiment of the invention, the additional active agent is included in a dose of about 5 μ g/kg to about 50 mg/kg. In other embodiments, the additional active agent may be included in a dose of about 5 μ g/kg to about 30mg/kg, about 5 μ g/kg to about 20mg/kg, or about 5 μ g/kg to about 10 mg/kg. In still other embodiments, the additional active agent can be included in a dose of about 10 μ g/kg to about 1mg/kg or about 50 μ g/kg to about 500 μ g/kg of animal weight. In still another embodiment of the present invention, the additional active agent is included in a dose of between about 0.1mg/kg to about 10mg/kg of animal weight. In yet another embodiment of the invention, the additional active agent is included in a dose of between 0.5mg/kg and 50 mg/kg.
The weight ratio of arylpyrrole (arylazol) -2-yl-cyanoethylamino compound and additional active agent is, for example, between about 5/1 and about 10,000/1. However, one of ordinary skill in the art will be able to select the appropriate ratio of arylpyrrole (arylazol) -2-yl-cyanoethylamino compound and additional active agent for the intended host and its use.
Preparation method
Another aspect of the present invention is a process for the preparation of the novel anthelmintic compounds of the present invention. The compounds of the invention may be prepared according to the methods described herein or by the use or adaptation of known methods, i.e. the methods used or described to date in the chemical literature. For example, in certain embodiments, the compounds of the invention may be prepared by the methods described in WO 2009/077527 a1, WO 2010/115688 a1, WO 2010/146083 a1, and EP 2468096 a1 (all incorporated herein by reference) or by adaptation of the methods described in these publications.
Abbreviation table:
AIBN azobisisobutyronitrile
BINAP 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl
BSA bovine serum albumin
BOC tert-butoxycarbonyl
dba dibenzylidene acetone (dibenzylidene acetone)
CDI 1,1' -carbonyldiimidazole
CI chemical ionization
DEGMME diethylene glycol monomethyl ether
DIAD diisopropyl azodicarboxylate
DIEA diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide
EDAC HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
ES electrospray ionization
EtOAc ethyl acetate
HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate
HBSS Hank's balanced salt solution
HOBt 1-hydroxybenzotriazole
NBS N-bromosuccinimide
NMM N-methylmorpholine
POM polyoxymethylene (Formaldehyde polymer)
TBAF tert-butylammonium fluoride
TBHP tert-butyl hydroperoxide
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran
EXAMPLE 1 preparation of N- [ 4-nitro-3- (trifluoromethyl) phenyl ] piperidin-4-amine
Step 1.4- [ [ 4-nitro-3- (trifluoromethyl) phenyl ] amino ] piperidine-1-carboxylic acid tert-butyl ester formation
Figure BDA0001193146030001331
To a solution of 4-fluoro-1-nitro-2- (trifluoromethyl) benzene (5g,24mmol) in DMSO (50ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (4.78g,23.9mmol, 1eq.) and potassium carbonate (9.9g,72mmol,3 eq.). The resulting mixture was stirred while heating at 100 ℃ (oil bath) overnight, then diluted with water (300 ml). The solid was collected by filtration to give 4- [ [ 4-nitro-3- (trifluoromethyl) phenyl ] as a yellow powder]Amino group]Piperidine-1-carboxylic acid tert-butyl ester (8g, 86%); (ES, M/z) < M + H]+390.0；1H NMR(300MHz, DMSO-d6):δ8.06(d,J＝9.3Hz,1H),7.47(d,J＝7.8Hz,1H), 7.08(d,J＝2.1Hz,1H),6.89(dd,J＝2.4,9.3Hz,1H),3.87(d, J＝13.5Hz,2H),3.68(m,1H),2.95(m,2H),2.54(s,0.6H),1.89 (m,2H),1.39(s,9H),1.28(m,2H)。
Step 2. formation of N- [ 4-nitro-3- (trifluoromethyl) phenyl ] piperidin-4-amine.
Figure BDA0001193146030001341
To 4- [ [ 4-nitro-3- (trifluoromethyl) phenyl]Amino group]To a solution of tert-butyl piperidine-1-carboxylate (1g,2.6mmol) in dichloromethane (10mL) was added trifluoroacetic acid (3 mL). The solution was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude material was diluted with water (50ml) and the pH adjusted to sodium bicarbonate (saturated aqueous solution)9 and extracted with dichloromethane (3X 100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N- [ 4-nitro-3- (trifluoromethyl) phenyl ] as a yellow powder]Piperidin-4-amine (800mg, crude); (ES, M/z) < M + H]+290.1；1H NMR(300MHz, DMSO-d6):δ8.08(d,J＝9.0Hz,1H),7.20-7.80(br s),7.60(d, J＝7.8Hz,1H),7.11(d,J＝2.4Hz,1H),6.91(dd,J＝2.4,9.0Hz, 1H),3.70(m,1H),3.22(d,J＝12.6Hz,2H),2.91(dd,J＝10.5, 11.4Hz,2H),1.99(d,J＝11.4Hz,2H),1.52(m,2H)。
EXAMPLE 2 preparation of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] piperidin-4-amine
Step 1.4- [ [ 4-cyano-3- (trifluoromethyl) phenyl ] amino ] piperidine-1-carboxylic acid tert-butyl ester formation.
Figure BDA0001193146030001342
To a solution of 4-fluoro-2- (trifluoromethyl) benzonitrile (5g,26mmol) in DMSO (50ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.3g,26.5mmol,1eq.) and potassium carbonate (7.3g,52.8mmol,2 eq.). The resulting solution was stirred while heating at 100 ℃ (oil bath) overnight. The resulting solution was diluted with ethyl acetate (300ml) and washed with sodium chloride (saturated, 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was applied to a silica gel column and eluted with ethyl acetate to give 4- [ [ 4-cyano-3- (trifluoromethyl) phenyl ] as a white powder]Amino group]Piperidine-1-carboxylic acid tert-butyl ester (5g, 51%). (ES, M/z) < M + H]+370.1。
Step 2 formation of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] piperidin-4-amine.
Figure BDA0001193146030001351
To 4- [ [ 4-cyano-3- (trifluoromethyl) phenyl]Amino group]To a solution of tert-butyl piperidine-1-carboxylate (150mg,0.41mmol) in dichloromethane (4mL) was added trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours and then concentrated under vacuumAnd (4) shrinking. The crude material was diluted with 100ml of EtOAc and washed with sodium bicarbonate (saturated aqueous solution) and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Recrystallization of the crude solid from EtOAc/PE afforded N- [ 4-cyano-3- (trifluoromethyl) phenyl ] as a yellow powder]Piperidin-4-amine (93.1mg, 85% yield); (ES, M/z) < M + H]+270.1；1H NMR (300MHz,CDCl3):δ7.69(d,J＝8.7Hz,1H),7.16(d,J＝7.8Hz, 1H),7.03(d,J＝1.2Hz,1H),6.85(dd,J＝2.1,8.7Hz,1H),3.42 (m,1H),2.94(m,2H),2.53(m,2H),1.82(d,J＝10.2Hz,2H), 1.27(m,2H)。
EXAMPLE 3 Synthesis of the Compound # 3: 4- [4- [ 2-oxo-2- [4- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] piperazin-1-yl ] ethoxy ] -1-piperidinyl ] -2- (trifluoromethyl) benzonitrile
Step 1: formation of 4- (4-hydroxy-1-piperidinyl) -2- (trifluoromethyl) benzonitrile
Figure BDA0001193146030001352
To a solution of 4-fluoro-2- (trifluoromethyl) benzonitrile (190mg,1mmol,1eq) in anhydrous DMF (5mL) was added potassium carbonate (276mg,2mmol,2 eq). 4- (4-hydroxy-1-piperidinyl) -2- (trifluoromethyl) benzonitrile (102mg,1mmol,1eq) was dissolved in DMF (5mL) and added to the existing solution. The reaction was heated to 80 ℃ in an aluminum block for 18 hours. With 25mL of H2The mixture was diluted O and extracted with 2X 25mL of EtOAc. The combined organic layers were then washed with saturated aqueous LiCl (50ml) and brine (50ml), dried over anhydrous sodium sulfate, filtered and dried under vacuum to give a residue which was applied to a silica gel column and eluted with heptane-EtOAc to give 4- (4-hydroxy-1-piperidinyl) -2- (trifluoromethyl) benzonitrile as a white solid (200mg, 74%).
Step 2.2 formation of tert-butyl- [ [1- [ 4-cyano-3- (trifluoromethyl) phenyl ] -4-piperidinyl ] oxy ] acetate.
Figure BDA0001193146030001361
A solution of 4- (4-hydroxy-1-piperidinyl) -2- (trifluoromethyl) benzonitrile (200mg,0.74 mmol,1eq) in THF (10ml) was cooled to 0 ℃ in an ice bath. 60% sodium hydride in mineral oil (90mg, 2.2mmol, 3eq) was added and the slurry was stirred for 15 minutes. Tert-butyl bromoacetate (293mg,1.5mmol,2eq) was added dropwise over 5 min and the resulting solution was allowed to warm slowly to room temperature. After 18 hours, the solution was cooled to 0 ℃ and then charged with 25mL of H2O is carefully quenched. The aqueous mixture was extracted with 2X 25mL of EtOAc. The combined organic layers were then washed with saturated NH4Aqueous Cl solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which is applied to a silica gel column and eluted with heptane-EtOAc to afford 2- [ [1- [ 4-cyano-3- (trifluoromethyl) phenyl ] as a white waxy solid]-4-piperidinyl group]Oxy radical]Tert-butyl acetate (100mg, 35%).
Step 3.2- [ [1- [ 4-cyano-3- (trifluoromethyl) phenyl ] -4-piperidinyl ] oxy ] acetic acid formation.
Figure BDA0001193146030001362
To a solution of tert-butyl 2- [ [1- [ 4-cyano-3- (trifluoromethyl) phenyl ] -4-piperidinyl ] oxy ] acetate (100mg,0.26mmol,1eq) in DCM (5ml) was added TFA (5 ml). The resulting solution was stirred for 2 hours and then concentrated in vacuo to an oil. The oil was diluted twice in 25mL of DCM and concentrated in vacuo to remove any residual TFA. A viscous oil was used in the following reaction, assuming 100% conversion.
Step 4: formation of 4- [4- [ 2-oxo-2- [4- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] piperazin-1-yl ] ethoxy ] -1-piperidinyl ] -2- (trifluoromethyl) benzonitrile compound # 3.
Figure BDA0001193146030001371
To 2- [ [1- [ 4-cyano-3- (trifluoromethyl) phenyl group]-4-piperidinyl group]Oxy radical]To a solution of acetic acid (85 mg,0.26mmol,1eq) in DMF (5ml) was added EDAC & HCl (75 m)g,0.39mmol,1.5eq), HOBt (60mg,0.39mmol,1.5eq) and 4-methylmorpholine (0.14ml,1.3mmol,5 eq). The resulting solution was stirred for 10 min, then 2-piperazin-1-yl-5-trifluoromethyl-benzothiazole (75mg, 0.26mmol,1eq) was added. The solution was stirred at room temperature overnight, diluted with EtOAc (50ml), washed with saturated aqueous LiCl (50ml) and brine (50ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude product was applied to a silica gel column and eluted with heptane-EtOAc to give a material which was subjected to reverse phase chromatography (H)2O-MeOH) to give 4- [4- [ 2-oxo-2- [4- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] as a white solid]Piperazin-1-yl]Ethoxy radical]-1-piperidinyl group]-2- (trifluoromethyl) benzonitrile (15.5mg, 9.9%). (ES, M/z) < M + H]+598；1H NMR(400MHz,CDCl3) δppm:1.68-1.86(m,2H),1.93-2.17(m,2H),3.12-3.36(m, 2H),3.50-3.95(m,11H),4.29(s,2H),6.96(dd,J＝8.8,2.4 Hz,1H),7.12(d,J＝2.1Hz,1H),7.36(d,J＝7.9Hz,1H),7.61 (d,J＝8.8Hz,1H),7.72(d,J＝8.2Hz,1H),7.81(s,1H)。
Example 4 preparation of 1-naphthalen-2-yl-piperazine hydrochloride.
Figure BDA0001193146030001381
A solution of naphthalen-2-amine (2g,14mmol) and bis (2-chloroethyl) amine hydrochloride (2.51g,14.1mmol,1eq) in diethylene glycol monoethyl ether (3mL) was stirred under 149 deg.C (oil bath) overnight. The resulting solution was diluted with methanol (2 ml). The crude product was recrystallized from diethyl ether to yield 1- (naphthalen-2-yl) piperazine hydrochloride (2g, 58%) as a yellow solid. (ES, M/z) < M + H]+213.0
Example 5 preparation of 6-fluoro-2- (piperazin-1-yl) quinoline.
Step 1. formation of cinnamoyl chloride.
Figure BDA0001193146030001382
In a round-bottomed flask, at 70 ℃ with SOCl2(150ml) treatment of cinnamic acid (2)5g, 168.74mmol) for 2 hours. The volatiles were distilled off under vacuum to give cinnamoyl chloride (25.2g, crude) as a yellow oil, which was used in the next step without further purification.
Step 2. formation of N- (4-fluorophenyl) cinnamamide.
Figure BDA0001193146030001383
In a round bottom flask, a solution of crude cinnamoyl chloride (25.2g) in dichloromethane (50ml) was added to a stirred mixture of pyridine (14.4g,182mmol) and 4-dimethylaminopyridine (1.44g,11.8mmol) in dichloromethane (100ml) at 0 ℃ and stirred for 15 minutes, after which a solution of 4-fluoroaniline (13.2g, 118.79mmol) in dichloromethane (50ml) was added over 20 minutes. After stirring at room temperature for 3 hours, the mixture was quenched with water (500ml) and extracted with dichloromethane (3X 150 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography (eluting with 1-5% ethyl acetate in petroleum). The product-containing fractions were combined to give N- (4-fluorophenyl) cinnamamide as a pale yellow solid (17.8g, 61%); (ES, M/z) < M + H]+242；1H NMR(300MHz,CDCl3):δ10.28(s,1H), 7.70-7.75(m,5H),7.39-7.65(m,3H),7.15(t,J＝9.0Hz,2H),6.79(d,J＝15.6Hz,1H)。
Step 3.6 formation of fluoro-1, 2-dihydroquinolin-2-one.
Figure BDA0001193146030001391
A direct mixture of N- (4-fluorophenyl) cinnamamide (10g,42mmol) and aluminium trichloride (16.4g, 123mmol,3eq) was melted by rapid heating and then heated at 100 ℃ for 3 hours. After cooling to room temperature, ice-water was added and the resulting precipitate was washed with water (300ml) and then with 5% aqueous hydrochloric acid (3 × 100ml) to give 6-fluoro-1, 2-dihydroquinolin-2-one as a brown solid (7.8g, 88%), which was used without further purification; (ES, M/z) < M + H]+164；1H NMR (300MHz, DMSO): δ 11.82 (width s,1H), 7.86(d, J ═ 9.4Hz,1H),7.61(d, J ═ 8.7Hz,1H),7.29 to 7.40(m, 2H),6.54(d, J ═ 9.4Hz, 1H).
Step 4.2-chloro-6-fluoroquinoline formation.
Figure BDA0001193146030001392
6-fluoro-1, 2-dihydroquinolin-2-one (7.8g, 47.8mmol) is suspended in phosphorus oxychloride (72.2g, 470.9mmol) and stirred in an oil bath at 100 ℃ for 4 hours. The reaction mixture was concentrated under vacuum to remove excess phosphoryl chloride, then ice-water (200ml) was added. The precipitate formed was washed with water (2X 80ml) and dried to give 2-chloro-6-fluoroquinoline as an off-white solid (6.8g, 78%); (ES, M/z) < M + H]+182；1H NMR (300MHz,DMSO):δ8.43(d,J＝8.4Hz,1H),8.01(dd,J＝5.4Hz, 9.3Hz,1H),7.87(dd,J＝3.0Hz,9.3Hz,1H),7.72-7.78(m,1H), 7.45(d,J＝8.4Hz,1H)。
Step 5: 6-fluoro-2- (piperazin-1-yl) quinoline formation.
Figure BDA0001193146030001393
To a solution of 2-chloro-6-fluoroquinoline (6.8g,37.4mmol) in N, N-dimethylformamide (200ml) was added potassium carbonate (10.4g,75.2 mmol) and piperazine (19.2g,222.9mmol) at room temperature in a round-bottom flask. After heating the contents to 130 ℃ for 5 hours, the reaction mixture was concentrated in vacuo, then quenched with water (300ml) and extracted with dichloromethane (3 × 200 ml). The combined organic layers were washed with brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 1-2.5% methanol in dichloromethane. The product containing fractions were combined and concentrated to give 6-fluoro-2- (piperazin-1-yl) quinoline (4.5g, 52%) as a brown solid; (ES, M/z) < M + H]+232；1H NMR(300MHz,CDCl3):δ7.86(d,J＝9.3Hz,1H), 7.62-7.72(m,1H),7.32-7.36(m,1H),7.24-7.29(m,1H),7.01 (d,J＝9.3Hz,1H),3.73(t,J＝5.1Hz,4H),3.05(t,J＝5.1Hz, 4H)。
Example 6 preparation of 2- (piperazin-1-yl) -6- (trifluoromethyl) quinoline.
Step 1.3, formation of 3-diethoxypropionic acid.
Figure BDA0001193146030001401
To a solution of ethyl 3, 3-diethoxypropionate (20g,105mmol) in water (80ml) was added sodium hydroxide (5g,125mmol,1.2 eq). The resulting solution was stirred in an oil bath at 110 ℃ for 1 hour and then adjusted to pH 5 with aqueous hydrogen chloride (3N). The crude product was then extracted with tetrahydrofuran (3 × 80ml) and the organic layers were combined, dried over anhydrous sodium sulfate and filtered, before being concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 3-50% ethyl acetate in petroleum ether. The product containing fractions were combined and concentrated in vacuo to afford 3, 3-diethoxypropionic acid (12g, 70%) as a pale yellow oil;1H NMR (300MHz,DMSO):δ4.80-4.82(t,J＝5.7Hz,1H),3.41-3.61(m, 4H),2.49(d,J＝5.7Hz,2H),1.06-1.24(m,6H)。
step 2 formation of (2E) -3-ethoxyprop-2-enoyl chloride.
Figure BDA0001193146030001402
3, 3-diethoxypropionic acid (5g,30.83mmol) was added to thionyl chloride (20ml) with stirring at 0 ℃ and then heated to 80 ℃ for 1 hour (oil bath). The resulting mixture was then concentrated in vacuo to give (2E) -3-ethoxyprop-2-enoyl chloride (4g, crude) as a dark red oil.
Step 3 formation of (2E) -3-ethoxy-N- (4-methylphenyl) prop-2-enamide.
Figure BDA0001193146030001411
To a solution of 4- (trifluoromethyl) aniline (2.56g,15.9mmol) in dichloromethane (40ml) was added pyridine (3.77g,47.7 mmol). Dissolving the mixture in waterThe solution was cooled to 0 ℃ and then 3, 3-diethoxypropionyl chloride (4g, crude material) in dichloromethane (10ml) was added dropwise with stirring. The resulting solution was stirred at 20 ℃ for 4 hours and then washed with water (200 ml). The resulting mixture was extracted with dichloromethane (3 × 80ml), the organic layers were combined and concentrated in vacuo. The crude residue was purified by prep-TLC eluting with 1-20% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated in vacuo to give (2E) -3-ethoxy-N- (4-trifluoromethylphenyl) prop-2-enamide (4.0g) as a yellow solid. (ES, M/z) < M + H]+260；1H NMR(300MHz,DMSO):δ10.10(s,1H),7.83(d, J＝8.4Hz,2H),7.72(s,1H),7.60(d,J＝8.7Hz,1H),7.50-7.56 (m,1H),5.52(d,J＝12.4Hz,1H),3.90-4.01(m,2H),1.15-1.30(m,3H)。
Step 4.6- (trifluoromethyl) -1, 2-dihydroquinolin-2-one formation.
Figure BDA0001193146030001412
(2E) -3-ethoxy-N- (4-trifluoromethylphenyl) prop-2-enamide (3.44g, 16.8mmol) was added in several portions to sulfuric acid (20ml) at 0 ℃ and then stirred at 0 ℃ for 2 hours. The resulting mixture was quenched with ice-water (100 ml). The product was precipitated from water and collected by filtration to give 6- (trifluoromethyl) -1, 2-dihydroquinolin-2-one (2.0g, 56%) as a yellow solid. (ES, M/z) < M + H]+214.1H NMR(300MHz,DMSO):δ8.14 (s,1H),8.03(d,J＝9.6Hz,1H),7.80-7.83(m,1H),7.45(d, J＝8.4Hz,1H),6.61-6.65(t,J＝9.6Hz,1H)。
Step 5.2-chloro-6- (trifluoromethyl) quinoline formation.
Figure BDA0001193146030001421
6- (trifluoromethyl) -1, 2-dihydroquinolin-2-one (1.0g, 4.7mmol) was dissolved in POCl3(15ml) and stirred in 110 deg.C (oil bath) for 2 hours. The resulting mixture was dissolved in ice-water (100ml) and Na was added2CO3The pH of the aqueous solution (3N) was adjusted to 8. Then, dichloromethane (3 is prepared80ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2-chloro-6- (trifluoromethyl) quinoline (944mg, 87%) as a dark red solid. (ES, M/z) < M + H]+232.1H NMR(300MHz, DMSO):δ8.59-8.66(m,2H),8.01-8.17(m,2H),7.75(d,J＝8.7 Hz,1H)。
Step 6: formation of 2- (piperazin-1-yl) -6- (trifluoromethyl) quinoline.
Figure BDA0001193146030001422
To a solution of 2-methyl-6- (trifluoromethyl) quinoline (1.5g,7.10mmol) in N, N-dimethylformamide (50ml) were added piperazine (2.8g,32.51mmol) and potassium carbonate (1.8g,12.93 mmol). The resulting solution was stirred at 140 ℃ for 3 hours and then quenched by the addition of water (200 ml). The crude product was extracted with ethyl acetate (3X 100ml) and the organic layers were combined. The resulting mixture was washed with saturated aqueous sodium chloride (3 × 100ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by chromatography on silica gel eluting with 1-5% methanol in dichloromethane. The product-containing fractions were combined and concentrated to give 2- (piperazin-1-yl) -6- (trifluoromethyl) quinoline (1.3g, 65%) as a brown solid. (ES, M/z) < M + H]+282；1H NMR(300MHz,DMSO):δ8.17-8.23 (t,J＝9.3,2H),7.66-7.77(m,2H),7.63(d,J＝9.3Hz,1H), 3.78-3.81(t,J＝4.5Hz,4H),2.92-2.96(t,J＝4.5Hz,4H).
Example 7 preparation of 1- (5-fluoro-2, 3-dihydro-benzofuran-2-ylmethyl) -piperazine.
Step 1.1 formation of 1-allyloxy-4-fluorobenzene.
Figure BDA0001193146030001431
To a 1L round bottom flask containing 500ml of acetonitrile were added 4-fluorophenol (30.0g, 267.6mmol), 3-bromoprop-1-ene (41.7g,344.7mmol,1.3eq), and potassium carbonate (55g,398mmol,1.5 eq). The mixture was stirred at 60 deg.C (oil bath) for 3.5 hours. The solid was filtered off and the filtrate was concentrated in vacuo to give 25.0 g of crude product as a yellow oil; 61 percent.
Step 2.2-allyl-4-fluoro-phenol formation.
Figure BDA0001193146030001432
In a 250ml round bottom flask, 1-allyloxy-4-fluorobenzene (23.0g, 151mmol) was heated at 260 ℃ for 5 hours. The crude product was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate. The product-containing fractions were concentrated in vacuo to give 18.0 g (78%) of a yellow oil.
Step 3.5 formation of fluoro-2-iodomethyl-2, 3-dihydrobenzofuran.
Figure BDA0001193146030001433
To a solution of 4-fluoro-2- (prop-2-en-1-yl) phenol (5g,32.9mmol) in dichloromethane (125mL) at room temperature was added SnCl4(4.28g,16.5mmol) and iodine (8.36g,32.9 mmol). After a further 18 hours, the reaction was quenched with water (150ml) and the pH was adjusted to-8 with aqueous sodium hydroxide (2N). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2X 100 mL). With Na2S2O4The combined organic layers were washed (3 × 100mL, 5%) to remove iodine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0.5-1% ethyl acetate in petroleum ether. The product containing fractions were combined and concentrated in vacuo to give 5-fluoro-2- (iodomethyl) -2, 3-dihydro-1-benzofuran as a yellow oil. (5g, 54%);1H NMR (300MHz,DMSO):δ7.03-7.08(dd,J＝5.7Hz,8.4Hz,1H), 6.93-6.86(dt,J＝2.7Hz,8.7Hz,1H),6.76-6.70(m,1H), 4.88-4.79(m,1H),3.49-3.60(m,2H),3.41-3.32(dd,J＝7.2Hz, 16.5Hz,1H),2.96-2.88(dd,J＝7.2Hz,16.5Hz,1H)。
step 4.1 formation of- (5-fluoro-2, 3-dihydro-benzofuran-2-ylmethyl) -piperazine.
Figure BDA0001193146030001441
To a 100ml round bottom flask containing 40ml of acetonitrile were added 5-fluoro-2-iodomethyl-2, 3-dihydro-benzofuran (5.7g,20.5mmol), piperazine (6.6g,76.6mmol, 4eq) and potassium carbonate (4.2g,30.4mmol,1.5 eq). The mixture was stirred at room temperature for 4 hours. The reaction contents were diluted with water and then extracted with 3X 200ml of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude material was then purified by chromatography on silica gel eluting with methanol/dichloromethane. Thereafter, the product containing fractions were concentrated in vacuo to give 2.2g (45%) of substituted piperazine as a dark red oil.
EXAMPLE 8 preparation of 2-chloro-1- [4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethan-1-one.
Step 1.1 formation of- [4- (trifluoromethyl) phenyl ] piperazine.
Figure BDA0001193146030001442
1-bromo-4- (trifluoromethyl) benzene (15g,67 mmol), piperazine (28.8g,334.4mmol,5eq.), Pd were stirred at 70 ℃ under nitrogen2(dba)3A mixture of (1.4g,1.53 mmol,2 mol%), BINAP (420mg,0.67mmol,1 mol%) and t-BuONa (12.9 g,134.2mmol,2eq.) in toluene (200ml) for 2 hours. Then, the solid was filtered off and the mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography using 1% to 5% methanol in dichloromethane to give 1- [4- (trifluoromethyl) phenylpiperazine (10.5g, 68%) as a dark red solid. (ES, M/z) < M + H]+231.1；1H NMR(300MHz,CDCl3):δ7.48(d,J＝8.7Hz,2H),6.92(d,J＝8.7 Hz,2H),3.32-3.20(m,4H),3.04-3.01(m,4H)。
Step 2.2 formation of 2-chloro-1- [4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl ] ethan-1-one.
Figure BDA0001193146030001451
To 1- [4- (trifluoromethyl) phenyl at 0 DEG C]To a mixture of piperazine (600mg,2.61mmol) and triethylamine (660mg,6.52mmol) in dichloromethane (20ml) was added 2-chloroacetyl chloride (380mg,3.36mmol) dropwise. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was then quenched with water (80ml) and extracted with dichloromethane (3 × 30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 1% -10% ethyl acetate in petroleum ether to give 2-chloro-1- [4- [4- (trifluoromethyl) phenyl ] as a white solid]Piperazin-1-yl]Ethan-1-one (479mg, 60%). (ES, M/z) < M + H]+307.1；1H NMR(300MHz,CDCl3):δ7.52(d,J＝8.4Hz,2H),6.97(d,J＝8.7Hz,2H),4.12(s,1H),3.81 (t,J＝5.1Hz,2H),3.72(t,J＝5.1Hz,2H),3.36(t,J＝5.1Hz, 2H),3.30(t,J＝5.1Hz,2H)。
Example 9 preparation of 7-amino-8- (trifluoromethyl) naphthalen-2-ol.
Step 1.7 formation of Methoxynaphthalen-2-ol.
Figure BDA0001193146030001452
Naphthalene-2, 7-diol (25g,156.08mmol) and K were added with stirring at 0 deg.C2CO3(32.3g,232.02mmol) in acetone (300ml) was added methyl iodide (22.2g, 156.41mmol) dropwise. The resulting solution was stirred at room temperature overnight. The solid was filtered off and the filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 1% to 10% ethyl acetate in petroleum ether to give 7-methoxynaphthalen-2-ol (10g, 37%) as a pale yellow solid. (ES, M/z) < M + H]+175.1；1H NMR(400MHz,DMSO-d6): δ9.65(s,1H),7.65(d,J＝8.8Hz,2H),6.79(dd,J＝13.6,1.6 Hz,2H),6.92-6.89(m,2H),3.84(s,3H)。
Step 2.7 formation of methoxynaphthalen-2-amine.
Figure BDA0001193146030001461
Secret inIn a sealed tube, 7-methoxynaphthalen-2-ol (6.5g,37.31mmol) and NaHSO were stirred at 140 deg.C3A solution of (11.6g,111.54mmol) in ammonium hydroxide (100ml) for 2 days, then cooled to room temperature. The solid was collected by filtration to give 7-methoxynaphthalen-2-amine (4.5g, 70%) as an off-white solid. (ES, M/z) < M + H]+174.1；1H NMR(300MHz,CDCl3): δ7.57(d,J＝8.7Hz,2H),6.97-6.87(m,3H),6.79(dd,J＝8.7, 2.1Hz,1H),3.90(s,3H),3.84(br s,2H)。
Step 3.1 formation of 1-iodo-7-methoxynaphthalen-2-amine.
Figure BDA0001193146030001462
To a mixture of 7-methoxynaphthalen-2-amine (5g,29mmol) and sodium carbonate (6.1g, 57.6mmol) in tetrahydrofuran (200ml) and water (20ml) was added iodine (7.0g, 27.67mmol) portionwise at 0 ℃. The resulting solution was stirred at room temperature overnight, then diluted with water (250ml) and extracted with ethyl acetate (3X 200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to give 1-iodo-7-methoxynaphthalen-2-amine (5.2g, 60%) as a yellow solid. (ES, M/z) < M + H]+300.1；1H NMR (300MHz,CDCl3):δ7.54(dd,J＝8.7,5.4Hz,2H),7.30(d,J＝2.4 Hz,1H),6.91(dd,J＝8.7,2.4Hz,1H),6.84(d,J＝8.4Hz,1H), 4.04(br s,2H),3.96(s,3H)。
Step 4.1 formation of 1-iodo-7-methoxy-2-nitronaphthalene.
Figure BDA0001193146030001463
To a solution of 1-iodo-7-methoxynaphthalen-2-amine (10g,33.43mmol) and potassium iodide (300mg,1.81mmol) in acetonitrile (150mL) was added TBHP (12 mL) dropwise with stirring. The resulting solution was refluxed for 3 days and then saturated Na was added2S2O3The aqueous solution (50ml) was quenched and extracted with ethyl acetate (3X 150 ml). The combined organic layers were dried over anhydrous magnesium sulfate,filtration and concentration under vacuum gave a residue which was purified by silica gel column chromatography using 1% to 10% ethyl acetate in petroleum ether to give 1-iodo-7-methoxy-2-nitronaphthalene (2.5g, 23%) as a yellow solid.1H NMR(300MHz,CDCl3):δ7.86(d,J＝8.7 Hz,1H),7.78(dd,J＝9.0,1.8Hz,1H),7.68(d,J＝2.4Hz,1H),7.54(dd,J＝8.7,1.8Hz,1H),7.78(dd,J＝9.0,2.4Hz,1H),4.04 (s,3H)。
Step 5.7 formation of methoxy-2-nitro-1- (trifluoromethyl) naphthalene.
Figure BDA0001193146030001471
A mixture of 1-iodo-7-methoxy-2-nitronaphthalene (3.7g,11.24 mmol), CuI (2.3g,12.08mmol) and KF (1g,17.24mmol) in N, N-dimethylformamide (50ml) was stirred at 120 ℃ for 0.5 hour, after which 2, 2-difluoro-2- (fluorosulfonyl) acetate (2.3g, 11.97mmol) was added. The resulting solution was stirred at 120 ℃ for a further 0.5 h and then quenched with water (300 ml). The crude product was extracted with dichloromethane (3X 100ml) and the organic fractions were combined and washed with brine (3X 150 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue which was purified by silica gel column chromatography using 1% to 10% ethyl acetate in petroleum ether to give 7-methoxy-2-nitro-1- (trifluoromethyl) naphthalene (2g, 66%) as an off-white solid.1H NMR(300MHz,DMSO): δ8.48(d,J＝8.7Hz,1H),8.21(d,J＝9.3Hz,1H),7.84(d,J＝8.7 Hz,1H),7.56(dd,J＝9.0,2.1Hz,1H),7.41(s,1H),3.96(s, 3H)。
Step 6.7-amino-8- (trifluoromethyl) naphthalen-2-ol formation.
Figure BDA0001193146030001472
To a solution of 7-methoxy-1- (trifluoromethyl) naphthalen-2-amine (2g, 8.29mmol) in dichloromethane (20ml) was added dropwise BBR with stirring at-78 deg.C3(4ml,42mmol,5 eq.). The resulting solution was stirred at room temperature overnight, then quenched with ice-water (50ml) and extracted with dichloromethane (3; (prepared in a volume of 50ml)50ml) was extracted. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 7-amino- (trifluoromethyl) naphthalen-2-ol as a brown solid (1.3g, 69%). (ES, M/z) [ M-H ]]-256.0；1H NMR(300MHz,DMSO-d6): δ10.16(s,1H),8.41(d,J＝8.7Hz,1H),8.13(d,J＝9.0Hz, 1H),7.73(d,J＝8.7Hz,1H),7.47(s,1H),7.40(dd,J＝9.0,2.1 Hz,1H)。
EXAMPLE 10 preparation of 2-chloromethyl-5-trifluoromethyl-benzoxazole.
Step 1.2-amino-4-trifluoromethylphenol formation.
Figure BDA0001193146030001481
2-Nitro-4-trifluoromethylphenol (340mL,2.41mmol) was dissolved in methanol (50mL) and passed through H-Cube with a 10% Pd/C cartridge at ambient temperature and pressure. The eluate was concentrated under reduced pressure to give 2-amino-4-trifluoromethylphenol (438mg, 100%) as a pale brown solid. (CI, M/z) < M + H]+178,[M-H]-176；1H NMR(CDCl3):δ6.96(d,J＝2.0Hz,1H),6.89-6.94(m,1H),6.74(d, J＝8.2Hz,1H),4.10(br s,2H)。
Step 2 formation of 2-chloromethyl-5-trifluoromethyl-benzoxazole.
Figure BDA0001193146030001482
2-chloro-1, 1, 1-triethoxyethane (410mL,2.15mmol) was added to a suspension of 2-amino-4-trifluoromethylphenol (370mg, 1.79mmol) in acetic acid (7 mL); during the addition, the solution began to clarify. The solution was heated at 120 ℃ (external temperature). After 3 hours, the reaction mixture was cooled and the volatiles were removed under reduced pressure. Purification by silica gel chromatography eluting with a gradient of 0 to 10% ethyl acetate in heptane gave 2-chloromethyl-5-trifluoromethyl-benzoxazole (324mg, 77%) as a yellow oil. (CI, M/z) < M + H]+236；1H NMR(CDCl3):δ8.05(s,1H),7.66-7.73(m,2H),4.79(s, 2H)；19F NMR(376MHz,CDCl3):δppm-61.26(s,3F)。
Example 12 preparation of 5-fluoro-2- (piperazin-1-ylmethyl) -1, 3-benzothiazole.
Step 1.2- (bromoethyl) -5-fluoro-1, 3-benzothiazole formation
Figure BDA0001193146030001491
A mixture of 5-fluoro-2-methyl-1, 3-benzothiazole (500mg,2.99 mmol), NBS (600mg,3.37mmol) and AIBN (125mg,0.76mmol) in carbon tetrachloride (25ml) was heated at reflux for 20 hours with stirring under nitrogen. Then, the solution was concentrated to give a residue, which was purified by silica gel column chromatography using 1% ethyl acetate in petroleum ether to give 2- (bromoethyl) -5-fluoro-1, 3-benzothiazole as a yellow solid (150mg, 20%).1H NMR(400MHz,CDCl3):δ7.81(dd,J＝8.8,5.2Hz,1H),7.70 (dd,J＝9.2,2.4Hz,1H),7.23-7.16(m,1H),4.80(s,2H)。
Step 2.5 formation of fluoro-2- (piperazin-1-ylmethyl) -1, 3-benzothiazole.
Figure BDA0001193146030001492
A mixture of 2- (bromoethyl) -5-fluoro-1, 3-benzothiazole (150mg,0.61mmol), potassium carbonate (253mg,1.83mmol) and piperazine (263mg,3.05mmol) in acetonitrile (30ml) was heated under reflux for 4.5 hours with stirring and then concentrated in vacuo. The residue was dissolved in dichloromethane (100mL), washed with brine (3 × 50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 5-fluoro-2- (piperazin-1-ylmethyl) -1, 3-benzothiazole as a yellow crude solid (130 mg). (ES, M/z) < M + H]+252.1；1H NMR(400 MHz,CDCl3):δ7.81(dd,J＝8.8,5.2Hz,1H),7.70(dd,J＝9.6, 2.4Hz,1H),7.16-7.11(m,1H),3.93(s,2H),2.97-2.93(m,4H), 2.64-2.63(m,4H),1.98(s,1H)。
Example 13 preparation of 5-fluoro-2- (piperazin-1-yl) -1, 3-benzothiazole.
Step 1-2 formation of (3-fluorophenyl) thiourea
Figure BDA0001193146030001501
To a solution of ammonium thiocyanate (1.5g, 18mmol) in acetone (3mL) was added benzoyl chloride (2.3mL,18mmol) dropwise and stirred at room temperature for 15 min. Then, 3-fluoroaniline (2g, 18mmol) was added. The reaction mixture was diluted with acetone (3mL) and heated at reflux for 6 h. To this mixture was added a solution of sodium hydroxide (2.2g,55mmol) in water (14mL) and the yellow homogeneous solution was heated to reflux overnight. The reaction mixture was cooled and concentrated under reduced pressure to remove acetone. The mixture was adjusted to pH 5 with concentrated hydrochloric acid and then to pH 11 with aqueous ammonia to give a pale yellow precipitate which was filtered, washed with water (3X 10mL) and dried under vacuum to give (3-fluorophenyl) thiourea (1.4g, 42%) as a pale yellow solid.1HNMR(400MHz,DMSO-d6):δ9.84(s,1H),7.54(d,J＝11.6Hz, 1H),7.37-7.33(m,1H),7.16(d,J＝8.4Hz,1H),6.94-6.90(m, 1H)。
Step 3.5-fluoro-1, 3-benzothiazol-2-amine formation.
Figure BDA0001193146030001502
To a solution of bromine (1.22g, 7.6mmol) in dichloromethane (5mL) was added dropwise (3-fluorophenyl) thiourea (1.3g,7.6mmol) in dichloromethane (25mL) while maintaining the temperature below 30 ℃. The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The precipitate was collected to give 5-fluoro-1, 3-benzothiazol-2-amine (0.9g, 70%) as a white solid. (ES, M/z) < M + H]+169.0；1H NMR(400MHz,DMSO-d6):δ9.79 (br s,2H),7.97-7.91(m,1H),7.36-7.32(m,1H),7.21-7.16(m, 1H)。
Step 4.2-bromo-5-fluoro-1, 3-benzothiazole formation.
Figure BDA0001193146030001511
To 5-fluoro-1, 3-benzothiazol-2-amine: (900mg,5.35mmol) in acetonitrile (10mL) was added CuBR2(1.3g,5.88mmol) and isoamylnitrite (1g,8.55 mmol). The mixture was heated to reflux for 6 hours. The solution was poured into water (30mL) and extracted with ethyl acetate (3X 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2-bromo-5-fluoro-1, 3-benzothiazole as a pink solid (0.5 g, 40%). (ES, M/z) < M + H]+232.0；1H NMR(300MHz,CDCl3):δ 7.79-7.69(m,2H),7.29-7.19(m,1H)。
Step 4.5-fluoro-2- (piperazin-1-yl) -1, 3-benzothiazole formation.
Figure BDA0001193146030001512
To a solution of 2-bromo-5-fluoro-1, 3-benzothiazole (300mg,1.29mmol) in N, N-dimethylformamide (10mL) was added piperazine (560mg,6.50mmol) and potassium carbonate (537mg,3.89mmol) while stirring at 100 ℃ overnight. The mixture was poured into water (100mL) and extracted with dichloromethane (3X 50 mL). The organic layers were combined, washed with brine (3 × 50mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5-fluoro-2- (piperazin-1-yl) -1, 3-benzothiazole as an off-white solid (200mg, 65%). (ES, M/z) < M + H]+238.0；1H NMR(400MHz,CDCl3):δ7.51 (dd,J＝8.7,5.4Hz,1H),7.26(dd,J＝10.2,2.7Hz,1H),6.87-6.80 (m,1H),3.69-3.62(m,4H),3.05-3.01(m,4H)。
EXAMPLE 14 preparation of 4- [4- [ 2-oxo-2- [3- [ [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] amino ] azetidin-1-yl ] ethoxy ] -1-piperidinyl ] -2- (trifluoromethyl) benzonitrile compound # 4.
Step 1.3- [ [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] amino ] azetidine-1-carboxylic acid tert-butyl ester formation.
Figure BDA0001193146030001521
2-chlorobenzothiazole (690mg,2.90mmol) was mixed with 1-Boc-azetidine (500mg,2.90mmol,1eq.) and potassium carbonate (802mg,5.85mmol,2eq.) in 11ml DMF and stirred at room temperature overnight. The crude reaction contents were diluted with EtOAc, washed with water, saturated aqueous LiCl, then brine, and then dried over sodium sulfate. The crude material was then concentrated by rotary evaporation and purified by silica gel chromatography (EtOAc/heptane) to give 285mg (26%) of tert-butyl 3- [ [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] amino ] azetidine-1-carboxylate.
Step 2. formation of N- (azetidin-3-yl) -5- (trifluoromethyl) -1, 3-benzothiazol-2-amine.
Figure BDA0001193146030001522
4M hydrogen chloride in dioxane (3.4ml) was added to a stirred solution of N-Boc azetidine (127 mg, 0.34mmol) in 3.4ml 1, 4-dioxane. Concentration by rotary evaporation at 1 hour gave 148mg of crude N- (azetidin-3-yl) -5- (trifluoromethyl) -1, 3-benzothiazol-2-amine as a white solid.
Step 3.4- [4- [ 2-oxo-2- [3- [ [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] amino ] azetidin-1-yl ] ethoxy ] -1-piperidinyl ] -2- (trifluoromethyl) benzonitrile compound # 4.
Figure BDA0001193146030001531
Diisopropylethylamine (110. mu.l, 0.6mmol) was added to a stirred solution of azetidine (74mg, 0.24mmol), carboxylic acid (77mg,0.24mmol) and HATU (91mg,0.24mmol) in 1ml of DMF. Stir at room temperature for 1 hour and dilute the crude reaction contents with EtOAc, wash with water, saturated aqueous LiCl, then brine, and then dry over sodium sulfate. The crude material was then concentrated by rotary evaporation and purified by silica gel chromatography (EtOAc/heptane) to yield 67mg of 4- [4- [ 2-oxo-2- [3- [ [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] as a pale yellow solid]Amino group]Azetidin-1-yl]Ethoxy radical]-1-piperidinyl group]-2- (trifluoromethyl) benzonitrile (48%). (ES, m/z):[M+H]+584；1H NMR(400MHz,(DMSO-d6)δ:8.97(d,J＝5.9Hz,1H),7.95 (d,J＝8.2Hz,1H),7.79(d,J＝8.8Hz,1H),7.67(d,J＝1.2Hz, 1H),7.37(dd,J＝8.2,1.2Hz,1H),7.29(d,J＝2.4Hz,1H),7.23 (dd,J＝8.9,2.5Hz,1H),4.62-4.68(m,1H),4.56-4.61(m,1H), 4.22-4.31(m,1H),4.14(dd,J＝9.1,4.8Hz,1H),4.06(d,J＝2.6 Hz,2H),3.84(dd,J＝10.2,4.7Hz,1H),3.70-3.79(m,2H),3.63 (tt,J＝7.8,3.8Hz,1H),3.22-3.30(m,2H),1.90(br.s,2H),1.46-1.59(m,2H)。
EXAMPLE 15 preparation of 4- [3- [ 2-oxo-2- [4- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] piperazin-1-yl ] ethoxy ] azetidin-1-yl ] -2- (trifluoromethyl) benzonitrile compound # 6.
Figure BDA0001193146030001541
Diisopropylethylamine (300 μ l,1.67mmol) was added to a stirred solution of carboxylic acid (201mg,0.67 mmol), piperazine (217mg,0.67mmol) and HATU (254mg,0.67mmol) in 3ml DMF. Stir at room temperature for 1 hour and dilute the crude reaction contents with EtOAc, wash with water, saturated aqueous LiCl, then brine, and then dry over sodium sulfate. The crude material was then concentrated by rotary evaporation on Celite and purified by silica gel chromatography (EtOAc/heptane) to give 127mg of 4- [3- [ 2-oxo-2- [4- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl ] as a white solid]Piperazin-1-yl]Ethoxy radical]Azetidin-1-yl]-2- (trifluoromethyl) benzonitrile (32%). (ES, m/z): [ M + H ]]+570；1HNMR(400MHz,(DMSO-d6)δ:8.03(d,J＝8.2Hz, 1H),7.79(d,J＝8.6Hz,1H),7.74(d,J＝0.7Hz,1H),7.40(dd, J＝8.3,1.2Hz,1H),6.78(d,J＝2.2Hz,1H),6.69(dd,J＝8.6,2.3Hz,1H),4.52-4.59(m,1H),4.32(s,2H),4.26(dd,J＝8.9, 6.7Hz,2H),3.95(dd,J＝10.0,3.9Hz,2H),3.54-3.70(m,8H)。
Examples of biological Activity
Method A: screening methods for testing compounds for activity against Haemonchus contortus (Haemonchus contortus).
Twenty L1 haemonchus contortus larvae were added to each well of a microtiter plate containing nutrient medium and test compound in DMSO. Analysis was performed on day 4 to determine the extent of development of the larvae. Larvae exposed to DMSO alone served as controls. Compounds 3, 6, 12, 15, 43, 44, 45, 46, 47, 48, 49, &50 gave at least 90% inhibition of motility at test concentrations less than or equal to < 1 μ M when evaluated at the 4 day time point.
Method B: a screening method for determining the activity of a compound against microfilaria of heartworm (Dirofilaria immitis).
Microfilaria of heartworm is added to each well of a microtiter plate containing buffer and test compound in DMSO. Evaluation was performed at 24 hours to determine the survival rate of microfilaria. Microfilaria exposed to DMSO alone was used as a control. EC possessed by Compound 4350Value less than 5. mu.M, Compound 44 in Return&EC of 4750The value is less than 0.01 ppm.
Method C: permeability of the compound.
The permeability of compounds across epithelial cells that follow the gastrointestinal tract is an important limiting factor in the oral absorption and systemic availability of compounds. The permeability properties of New Chemical Entities (NCEs) were evaluated using an in vitro model using Caco-2/TC7 cells. For compounds administered orally, absorption depends on the intrinsic permeability of the transenteric epithelium and whether the active agent is a substrate or inhibitor of uptake or excretion of the transporter.
Permeability studies were performed as follows: under standard conditions, a pH gradient and a BSA gradient (standard tip medium (0.5% BSA at pH 6.5)/standard basal medium (5% BSA at pH7.4)) in the tip to outside of the substrate (a → B) direction; each condition most closely reflects the condition of the in vivo condition. The samples were deproteinized by adding 400. mu.l of acetonitrile to 200. mu.l of the sample followed by centrifugation at 1730g for 20-min. Compound dissolution after dilution of the stock solution in HBSS (starting from 10mM in DMSO), a final concentration of 20 μ M compound solution was prepared. The final concentration of DMSO was adjusted to 1%. Analysis conditions were as follows: the supernatant recovered after centrifugation was analyzed by LC/MS using a reverse phase column and a mobile phase delivering water (a) and acetonitrile (B) (each containing 0.1% formic acid) in a gradient of 0.3 ml/min.
The permeability of the standard compounds in an in vitro model of CACO-2/TC7 permeability is shown in Table 7. Each experiment (n) represents the average of 3 filtrations per experiment.
TABLE 7 permeability as determined in the CACO-2/TC7 model.
Figure BDA0001193146030001561
Compound CC-1 (described in WO) of the prior art2009/077527) in comparison, compound 15 was present in the intestinal cell model&43 is 200-300% more permeable, compounds 44, 45&46 was 300% higher.
***
Although preferred embodiments of the invention have been described in detail, it should be understood that the invention defined in the foregoing paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the invention.

Claims (12)

1. Anthelmintic compounds of formula (IA-1)
Figure FDA0002300687910000011
Wherein
Y is benzothiazolyl or benzoxazolyl, optionally independently substituted with one or more of the following groups: c1-C4Haloalkyl, C1-C4Haloalkoxy or C1-C4A haloalkylthio group; and Z is phenyl, optionally independently substituted with one or more of the following groups: cyano, halogen or C1-C4A haloalkyl group;
X1is a bond or-NH-;
X6is-O-;
X8is a bond;
one of Ring A and Ring B is L19
Figure FDA0002300687910000012
And the other of ring a and ring B is trans-cyclohexylene, L1, or L4:
Figure FDA0002300687910000013
wherein Q1、Q2、Q5And Q6Independently of each other is CH or N,
w is O;
R2and R3Is hydrogen;
m and q are both 0; and is
n is 1.
2. The anthelmintic compound of claim 1, wherein X1is-NH-.
3. The anthelmintic compound of claim 1 or 2, wherein Y is benzothiazolyl, substituted with one or more of the following groups: c1-C3Haloalkyl, C1-C3Haloalkoxy or C1-C3A haloalkylthio group; and Z is cyano, halogen or C1-C3Haloalkyl-substituted phenyl.
4. The anthelmintic compound of claim 1 or 2, wherein Y is benzoxazolyl, substituted with one or more of the following groups: c1-C3Haloalkyl, C1-C3Haloalkoxy or C1-C3A haloalkylthio group; and Z is cyano, halogen or C1-C3Haloalkyl-substituted phenyl.
5. The anthelmintic compound of claim 3 or 4, wherein Y is substituted with one or more CF3、OCF3Or SCF3Substituted benzothiazolyl or benzoxazolyl; and Z is substituted by one or more of the following groupsPhenyl group: CN, halogen or CF3。
6. The anthelmintic compound of any one of claims 1 to 5, wherein one of ring A and ring B is trans-cyclohexylidene or L1:
Figure FDA0002300687910000021
7. the anthelmintic compound of any one of claims 1 to 6, wherein
One of Ring A and Ring B is L4
Figure FDA0002300687910000022
8. The anthelmintic compound of claim 1, wherein:
y is substituted by one or more CF3、OCF3、SCF3Substituted benzothiazolyl or benzoxazolyl;
z is substituted by one or more fluorine, CN or CF3Substituted phenyl;
X1and X8Are all a bond;
X6is O;
R2and R3Are all H; and is
n is 1.
9. A composition for the treatment and prevention of a parasitic infection or infestation in an animal comprising an effective amount of at least one anthelmintic compound of any one of claims 1 to 8 in combination with a pharmaceutically acceptable carrier.
10. The composition of claim 9, wherein the composition comprises an additional parasiticidal active agent.
11. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment and prevention of endoparasitic nematode infections in non-human animals.
12. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of parasitic nematode infections in animals.
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